Carbodiimide coupling reagent

ABSTRACT

The present invention relates to compounds used for increasing activation of the 5-HT1F receptor.

CROSS REFERENCE

This application is a divisional of Ser. No. 09/043,360, filed Mar. 13,1998, still pending National Phase from PCT Application NumberPCT/US96/16122, which claims priority from U.S. Provisional Applications60/005,213 filed Oct. 10, 1995 and 60/015,851 filed May 22, 1996.

Theories regarding the pathophysiology of migraine have been dominatedsince 1938 by the work of Graham and Wolff (Arch. Neurol. Psychiatry,39, 737-63 (1938)). They proposed that the cause of migraine headachewas vasodilatation of extracranial vessels. This view was supported byknowledge that ergot alkaloids and sumatriptan, a hydrophilic 5-HT₁agonist which does not cross the blood-brain barrier, contract cephalicvascular smooth muscle and are effective in the treatment of migraine.(Humphrey, et al., Ann. NY Acad. Sci., 600, 587-600 (1990)). Recent workby Moskowitz has shown, however, that the occurrence of migraineheadaches is independent of changes in vessel diameter (Cephalalgia, 12,5-7, (1992)).

Moskowitz has proposed that currently unknown triggers for painstimulate trigeminal ganglia which innervate vasculature within thecephalic tissue, giving rise to release of vasoactive neuropeptides fromaxons on the vasculature. These released neuropeptides then activate aseries of events, a consequence of which is pain. This neurogenicinflammation is blocked by sumatriptan and ergot alkaloids by mechanismsinvolving 5-HT receptors, believed to be closely related to the5-HT_(1D) subtype, located on the trigeminovascular fibers (Neurology,43(suppl. 3), S16-S20 (1993)).

Serotonin (5-HT) exhibits diverse physiological activity mediated by atleast four receptor classes, the most heterogeneous of which appears tobe 5-HT₁. A human gene which expresses a fifth 5-HT₁ subtype, named5-HT_(1F), was isolated by Kao and coworkers (Proc. Natl. Acad. Sci.USA, 90, 408-412 (1993)). This 5-HT_(1F) receptor exhibits apharmacological profile distinct from any serotonergic receptor yetdescribed. The high affinity of sumatriptan at this subtype, K_(i) =23nM, suggests a role of the 5-HT_(1F) receptor in migraine.

This invention provides novel 5-HT_(1F) agonists which inhibit peptideextravasation due to stimulation of the trigeminal ganglia. Althoughstructurally similar compounds have been shown to be potentvasoconstrictors (U.S. Pat. No. 4,839,377), the compounds of the presentinvention exhibit no appreciable vasoconstrictive properties. The lackof vasoconstrictive properties, coupled with potent 5-HT_(1F) agonistactivity, distinguish the compounds of the present invention overstructurally similar compounds and currently available migrainetherapies.

The present invention provides a method for increasing activation of the5-HT_(1F) receptor by administering to a mammal in need of suchactivation a pharmaceutically effective amount of a compound of FormulaI: ##STR1## in which R¹ is hydrogen or C₁ -C₄ alkyl;

R² is C₁ -C₄ alkyl, C₃ -C₈ cycloalkyl, cycloalkyl-(C₁ -C₃ alkylene),aryl-(C₁ -C₃ alkylene), or heteroaryl-(C₁ -C₃ alkylene);

R³ is hydrogen or C₁ -C₄ alkyl;

X is R⁴ C(O)NH--, R⁵ R⁶ NC(Y)NH--, R⁷ OC(O)NH--, or R⁸ SO₂ NH--;

R⁴ is C₁ -C₄ alkyl, C₃ -C₇ cycloalkyl, phenyl, substituted phenyl,biphenylyl, naphthyl, or a heterocycle;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, C₁ -C₆ alkyl, C₃ -C₆ alkenyl, C₃ -C₈ cycloalkyl, phenyl,substituted phenyl, phenyl(C₁ -C₄ alkylene), phenyl(C₁ -C₄ alkylene)substituted in the phenyl ring, ((C₁ -C₄ alkyl or C₃ -C₄ alkoxcarbonylsubstituted)C₁ -C₄ alkyl)phenyl, C₁ -C₄ alkyl α-substituted with C₁ -C₄alkoxycarbonyl; or

R⁵ and R⁶ taken together with the nitrogen atom to which they areattached form a pyrrolidine, piperidine, piperazine, 4-substitutedpiperazine, morpholine or thiomorpholine ring;

R⁷ is C₁ -C₆ alkyl, C₃ -C₆ alkenyl, phenyl, substituted phenyl, C₃ -C₈cycloalkyl, C₁ -C₄ alkyl ω-substituted with C₁ -C₄ alkoxy;

R⁸ is C₁ -C₄ alkyl, phenyl, substituted phenyl, or di(C₁ -C₄alkyl)amino;

Y is S or O, and pharmaceutically acceptable acid addition saltsthereof.

A further embodiment of this invention are novel optionally substitutedN-[2-substituted-3-(2-aminoethyl)-1H-indol-5-yl]amides of Formula II:##STR2## in which R¹ is hydrogen or C₁ -C₄ alkyl;

R² is C₁ -C₄ alkyl, C₃ -C₈ cycloalkyl, cycloalkyl-(C₁ -C₃ alkylene),aryl-(C₁ -C₃ alkylene), or heteroaryl-(C₁ -C₃ alkylene);

R³ is hydrogen or C₁ -C₄ alkyl;

X is R⁴ C(O)NH--, R⁵ R⁶ NC(Y)NH--, R⁷ OC(O)NH--, or R⁸ SO₂ NH--;

R⁴ is C₁ -C₄ alkyl, C₃ -C₇ cycloalkyl, phenyl, substituted phenyl,biphenylyl, naphthyl, or a heterocycle;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, C₁ -C₆ alkyl, C₃ -C₆ alkenyl, C₃ -C₈ cycloalkyl, phenyl,substituted phenyl, phenyl(C₁ -C₄ alkylene), phenyl(C₁ -C₄ alkylene)substituted in the phenyl ring, ((C₁ -C₄ alkyl or C₁ -C₄ alkoxycarbonylsubstituted)C₁ -C₄ alkyl)phenyl, C₁ -C₄ alkyl α-substituted with C₁ -C₄alkoxycarbonyl; or

R⁵ and R⁶ taken together with the nitrogen atom to which they areattached form a pyrrolidine, piperidine, piperazine, 4-substitutedpiperazine, morpholine or thiomorpholine ring;

R⁷ is C₁ -C₆ alkyl, C₃ -C₆ alkenyl, phenyl, substituted phenyl, C₃ -C₈cycloalkyl, C₁ -C₄ alkyl ω-substituted with C₁ -C₄ alkoxy;

R⁸ is C₁ -C₄ alkyl, phenyl, substituted phenyl, or di(C₁ -C₄alkyl)amino;

Y is S or O, and pharmaceutically acceptable acid addition salts thereofsubject to the following provisos:

1) R¹ and R³ may be hydrogen only when R² is heteroaryl(C₁ -C₄alkylene); and

2) X may be R⁵ R⁶ NC(Y)NH--, R⁷ OC(O)NH--, or R⁸ SO₂ NH-- only when R²is heteroaryl(C₁ -C₄ alkylene).

This invention also provides a pharmaceutical formulation whichcomprises, in association with a pharmaceutically acceptable carrier,diluent or excipient, a compound of Formula II.

A further embodiment of this invention is a method for increasingactivation of the 5-HT_(1F) receptor for treating a variety of disorderswhich have been linked to decreased neurotransmission of serotonin inmammals. Included among these disorders are depression, migraine pain,bulimia, premenstrual syndrome or late luteal phase syndrome,alcoholism, tobacco abuse, panic disorder, anxiety, general pain,post-traumatic syndrome, memory loss, dementia of aging, social phobia,attention deficit hyperactivity disorder, disruptive behavior disorders,impulse control disorders, borderline personality disorder, obsessivecompulsive disorder, chronic fatigue syndrome, premature ejaculation,erectile difficulty, anorexia nervosa, disorders of sleep, autism,mutism, allergic rhinitis, cold symptoms, trichotillomania, trigeminalneuralgia, dental pain or temperomandibular joint dysfunction pain. Thecompounds of this invention are also useful as a prophylactic treatmentfor migraine. Any of these methods employ a compound of Formula I.

The use of a compound of Formula I for the activation of the 5-HT_(1F)receptor, for the inhibition of peptide extravasation in general or dueto stimulation of the trigeminal ganglia specifically, and for thetreatment of any of the disorders described supra, are all embodimentsof the present invention.

This invention also provides the use of a compound of Formula II for themanufacture of a medicament for the prevention or treatment of migraineand associated disorders. Additionally, this invention provides apharmaceutical formulation adapted for the prevention or treatment ofmigraine containing a compound of Formula II. Furthermore, thisinvention includes a method for the prevention or treatment of migrainewhich comprises administering an effective amount of a compound ofFormula II.

The general chemical terms used in the formulae above have their usualmeanings. For example, the terms "alkyl, alkoxy and alkylthio" includesuch groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, and the like. The term "cycloalkyl" includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Theterm "acyl" includes formyl, acetyl, propanoyl, butanoyl, and2-methylpropanoyl. The term "(C₁ -C₄ alkyl)sulfonyl" includesmethanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl,butanesulfonyl and the like. The term "halogen" includes fluoro, chloro,bromo and iodo.

The term "substituted phenyl" is taken to mean a phenyl ring substitutedwith 1 to 3 substitutents independently selected from the groupconsisting of halogen, C₁ -C₄ alkoxy, C₁ -C₄ alkylthio, C₁ -C₄ alkyl, C₁-C₄ alkylsulfonyl, nitro, trifluoromethyl, N-(C₁ -C₄ acyl)amino, N-(C₁-C₄ alkyl)-N-(C₁ -C₄ acyl)amino, N,N-di(C₁ -C₄ alkyl)amino and C₁ -C₄alkoxycarbonyl.

The term "heterocycle" is taken to mean a thienyl, benzothienyl, furyl,benzofuryl, isobenzofuryl, pyrrolyl, 1-(C₁ -C₃ alkyl)pyrrolyl,imidazolyl, pyrazolyl, 1-(C₁ -C₃ alkyl)pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl,quinoxalinyl, thiazolyl, benzothiazolyl, oxazolyl, benzoxazolyl,1,3-benzodioxolyl, 1,4-benzodioxanyl, isoxazolyl, benzisoxazolyl,oxadiazolyl or triazolyl bonded through any available ring carbon atom.Each of these rings may be substituted on available ring carbon atomswith up to two substituents independently selected from the groupconsisting of halo, hydroxy, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄alkylthio, hydroxy substituted (C₁ -C₄ alkylene), cyano, carboxamido,nitro, amino, or di(C₁ -C₄ alkyl)amino.

The term "cycloalkyl-(C₁ -C₃ alkylene)" is taken to be an alkylene chainof 1-3 carbon atoms which may be monosubstituted with a methyl group andto which is bonded a C₃ -C₈ cycloalkyl moiety.

The term "aryl-(C₁ -C₃ alkylene)" is taken to be an alkylene chain of1-3 carbon atoms which may be monosubstituted with a methyl group and towhich is bonded a phenyl or substituted phenyl moiety.

The term "heteroaryl-(C₁ -C₃ alkylene)" is taken to be an alkylene chainof 1-3 carbon atoms optionally monosubstituted with a methyl group andto which is bonded a heterocycle.

The term "4-substituted piperazine" is taken to mean a piperazine ringsubstituted at the 4-position with a substituent selected from the groupconsisting of C₁ -C₆ alkyl, C₁ -C₄ alkoxy substituted C₁ -C₆ alkyl,phenyl, substituted phenyl, phenyl(C₁ -C₄ alkylene), phenyl(C₁ -C₄alkylene) substituted in the phenyl ring, heteroaryl, and heteroaryl(C₁-C₄ alkylene).

While all of the compounds of this invention are useful as 5-HT_(1F)agonists, certain classes are preferred. The following paragraphsdescribe such preferred classes.

aa) R¹ is methyl;

ab) R² is C₁ -C₄ alkyl;

ac) R² is methyl;

ad) R² is ethyl;

ae) R² is aryl-(C₁ -C₃ alkylene);

af) R² is 1-phenyl-1-ethyl;

ag) R² is 2-phenylethyl;

ah) R² is heteroaryl-(C₁ -C₃ alkylene);

ai) R² is 2-(1-(C₁ -C₄ alkyl)pyrazol-4-yl)ethyl;

aj) R² is (pyridin-2-yl)methyl;

ak) R² is 3-thienylmethyl;

al) R² is 3-indolylmethyl;

am) R² is 2-thienylmethyl;

an) R² is 2-furylmethyl;

ao) R² is (5-methylfur-2-yl)methyl;

ap) R² is (1-methylpyrrol-2-yl)methyl;

aq) R² is (5-hydroxymethylfur-2-yl)methyl;

ar) R² is (6-chloro-1,3-benzodioxol-5-yl)methyl;

as) R² is (3-methylbenzothien-2-yl)methyl;

at) R² is cycloalkyl-(C₁ -C₃ alkylene);

au) R³ is hydrogen;

av) R³ is C₁ -C₄ alkyl;

aw) R³ is methyl;

ax) X is R⁴ C(O)NH--;

ay) X is R⁵ R⁶ NC(Y)NH--;

az) X is R⁷ OC(O)NH--;

ba) X is R⁸ SO₂ NH--;

bb) R⁴ is C₁ -C₄ alkyl;

bc) R⁴ is C₃ -C₇ cycloalkyl;

bd) R⁴ is substituted phenyl;

be) R⁴ is phenyl;

bf) R⁴ is phenyl monosubstituted with halogen;

bg) R⁴ is 4-fluorophenyl;

bh) R⁴ is phenyl disubstituted with halogen;

bi) R⁴ is phenyl 2,6-disubstituted with halogen;

bj) R⁴ is phenyl 2,4-disubstituted with halogen;

bk) R⁴ is 2-chloro-4-fluorophenyl;

bl) R⁴ is phenyl trisubstituted with halogen;

bm) R⁴ is phenyl 2,4,6-trisubstituted with halogen;

bn) R⁴ is 2-methyl-4-fluorophenyl;

bo) R⁴ is a heterocycle;

bp) R⁴ is thienyl;

bq) R⁴ is furyl;

br) R⁵ is H;

bs) R⁶ is C₁ -C₄ alkyl;

bt) R⁶ is methyl;

bu) R⁶ is ethyl;

bv) R⁶ is propyl;

bw) R⁶ is isopropyl;

bx) R⁶ is phenyl;

by) R⁶ is C₃ -C₈ alkenyl;

bz) R⁶ is allyl;

ca) R⁶ is phenyl monosubstituted with halo;

cb) R⁶ is 4-fluorophenyl;

cc) R⁶ is 4-chlorophenyl;

cd) R⁶ is phenyl(C₁ -C₄ alkylene)

ce) R⁶ is benzyl;

cf) R⁶ is phenethyl;

cg) R⁵ and R⁶ taken together with the nitrogen to which they areattached form a morpholine ring;

ch) R⁵ and R⁶ taken together with the nitrogen to which they areattached form a thiomorpholine ring;

ci) R⁵ and R⁶ taken together with the nitrogen to which they areattached form a pyrrolidine ring;

cj) R⁵ and R⁶ taken together with the nitrogen to which they areattached form a piperidine ring;

ck) R⁵ and R⁶ taken together with the nitrogen to which they areattached form a pyrrolidine ring;

cl) R⁵ and R⁶ taken together with the nitrogen to which they areattached form a piperazine ring;

cm) R⁵ and R⁶ taken together with the nitrogen to which they areattached form a 4-substituted piperazine ring;

cn) R⁷ is C₁ -C₄ alkyl;

co) R⁷ is methyl;

cp) R⁷ is ethyl;

cq) R⁷ is propyl;

cr) R⁷ is C₃ -C₆ alkenyl;

cs) R⁷ is allyl;

ct) R⁷ is C₃ -C₈ cycloalkyl;

cu) R⁷ is cyclopentyl;

cv) R⁷ is phenyl monosubstituted with C₁ -C₄ alkoxy;

cw) R⁷ is 4-methoxyphenyl;

cx) R⁸ is C₁ -C₄ alkyl;

cy) R⁸ is methyl;

cz) R⁸ is ethyl;

da) R⁸ is phenyl;

db) R⁸ is di(C₁ -C₄ alkyl)amino;

dc) R⁸ is dimethylamino;

dd) Y is O;

de) The compound is a free base;

df) The compound is a salt;

dg) The compound is the hydrochloride salt;

dh) The compound is the fumarate salt;

di) The compound is the oxalate salt.

It will be understood that the above classes may be combined to formadditional preferred classes.

The compounds of this invention are useful in a method for increasingactivation of the 5-HT_(1F) receptor for treating a variety of disorderswhich have been linked to decreased neurotransmission of serotonin inmammals. It is preferred that the mammal to be treated by theadministration of compounds of this invention is human. It is alsopreferred that the compounds used for the method of the invention are ofFormula II.

Since the compounds of this invention are amines, they are basic innature and accordingly react with any of a number of inorganic andorganic acids to form pharmaceutically acceptable acid addition salts.Since some of the free amines of the compounds of this invention aretypically oils at room temperature, it is preferable to convert the freeamines to their pharmaceutically acceptable acid addition salts for easeof handling and administration, since the latter are routinely solid atroom temperature. Acids commonly employed to form such salts areinorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodicacid, sulfuric acid, phosphoric acid, and the like, and organic acids,such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, β-hydroxybutyrate, glycollate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate and the like. Preferredpharmaceutically acceptable salts are those formed with hydrochloricacid.

The following group is illustrative of compounds contemplated within thescope of this invention:

N-[2-methyl-3-(2-[N',N'-diethylamino]ethyl)-1H-indol-5-yl]-4-propanesulfonylbenzamidehydrochloride

N-[2-ethyl-3-(2-[N'-methyl-N'-isopropylamino]ethyl)-1H-indol-5-yl]-3-ethylthiobenzamidehydroiodide

N-[2-propyl-3-(2-[N'-ethyl-N'-cyclopentylpropylamino]-ethyl)-1H-indol-5-yl]-4-ethyl-2-propoxycarbonylbenzamidehydrobromide

N-[2-isopropyl-3-(2-[N',N'-dibutylamino]ethyl)-1H-indol-5-yl]-4-(N",N"-dipropylamino)benzamideoxalate

N-[2-n-butyl-3-(2-[N'-methyl-N'-benzylamino]ethyl)-1H-indol-5-yl]-4-isopropylbenzamidesulfate

N-[2-isobutyl-3-(2-[N'-methyl-N'-cyclopropylmethyl-amino]ethyl)-1H-indol-5-yl]-4-(N"-ethyl-N"-butanoyl)aminobenzamide acetate

N-[2-s-butyl-3-(2-[N'-methyl-N'-(2-[1-propylpyrazol-4-yl]ethyl)amino]ethyl)-1H-indol-5-yl]-2-nitrobenzamidephosphate

N-[2-t-butyl-3-(2-[N'-methyl-N'-(1-ethylpyrazol-4-ylmethyl)amino]ethyl)-1H-indol-5-yl]-4-isobutylsulfonylbenzamidemalonate

N-[2-methyl-3-(2-[N'-methyl-N'-isobutylamino]ethyl)-1H-indol-5-yl]-3-ethylbenzamidetartrate

N-[2-methyl-3-(2-[N'-methyl-N'-(2-[pyridin-4-yl]-ethyl)amino]ethyl)-1H-indol-5-yl]-3-t-butoxybenzamidecitrate

N-[2-methyl-3-(2-[N'-methyl-N'-s-butylamino]ethyl)-1H-indol-5-yl]-4-formylamino-2-propylbenzamide4-toluenesulfonate

N-[2-methyl-3-(2-[N'-methyl-N'-(2-[4-bromopyridin-3-yl]-ethyl)amino]ethyl)-1H-indol-5-yl]-3-t-butoxybenzamidebenzoate

N-[2-methyl-3-(2-[N'-methyl-N'-(2-[1-isopropylpyrazol-4-yl]ethyl)amino]ethyl)-1H-indol-5-yl]-4-isopropylthiobenzamidefumarate

N-[2-ethyl-3-(2-[N',N'-diethylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamidenaphthalene-1-sulfonate

N-[2-ethyl-3-(2-[N'-methyl-N'-isopropylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

N-[2-propyl-3-(2-[N'-ethyl-N'-cyclopentylpropylamino]-ethyl)-1H-indol-5-yl]-4-bromobenzamidephthalate

N-[2-isopropyl-3-(2-[N',N'-dibutylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamidemethanesulfonate

N-[2-n-butyl-3-(2-[N'-methyl-N'-benzylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

N-[2-isobutyl-3-(2-[N'-methyl-N'-cyclopropylmethylamino]ethyl)-1H-indol-5-yl]-4-iodobenzamidenaphthalene-1-sulfonate

N-[2-s-butyl-3-(2-[N'-methyl-N'-(2-[1-propylpyrazol-4-yl]ethyl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamideditoluoyltartrate

N-[2-t-butyl-3-(2-[N'-methyl-N'-(1-ethylpyrazol-4-ylmethyl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

N-[2-methyl-3-(2-[N'-methyl-N'-isobutylamino]ethyl)-1H-indol-5-yl]-2-bromo-4-fluorobenzamide

N-[2-methyl-3-(2-[N'-methyl-N'-(2-[pyridin-4-yl]-ethyl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

N-[2-methyl-3-(2-[N'-methyl-N'-s-butylamino]ethyl)-1H-indol-5-yl]-isobutyramide

N-[2-methyl-3-(2-[N'-methyl-N'-(2-[pyridin-4-yl]-ethyl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamidemalonate

N-[2-methyl-3-(2-[N'-methyl-N'-(2-[1-isopropylpyrazol-4-yl]ethyl)amino]ethyl)-1H-indol-5-yl]-butyramidemandelate

N-[3-(2-[N'-methyl-N'-([4-bromothien-2-yl]-methyl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamidehydrochloride

N-[2-ethyl-3-(2-[N'-ethyl-N'-(2-[3-methylthiobenzofur-5-yl]ethyl)amino]ethyl)-1H-indol-5-yl]pyridine-2-carboxamide

N-[2-propyl-3-(2-[N'-isopropyl-N'-(3-[isobenzofur-2-yl]-propyl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

N-[2-methyl-3-(2-[N'-butyl-N'-([pyrrol-3-yl]methyl)-amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamidemaleate

N-[2-methyl-3-(2-[N'-methyl-N'-([5-cyanoimidazol-2-yl]-methyl)amino]ethyl)-1H-indol-5-yl]acetamidetrifluoroacetate

N-[2-methyl-3-(2-[N'-methyl-N'-([6-carboxamidopyrazin-2-yl]methyl)amino]ethyl)-1H-indol-5-yl]propanamide

N-[2-methyl-3-(2-[N'-methyl-N'-([5-nitropyrimidin-2-yl]-methyl)amino]ethyl)-1H-indol-5-yl]-2-propanamide

N-[2-methyl-3-(2-[N'-methyl-N'-([5-dimethylaminopyridazin-3-yl]methyl)amino]ethyl)-1H-indol-5-yl]butyramidebenzoate

N-[2-methyl-3-(2-[N'-methyl-N'-([indazol-5-yl]methyl)-amino]ethyl)-1H-indol-5-yl]pentanamide

N-[2-methyl-3-(2-[N'-methyl-N'-([quinolin-4-yl]methyl)-amino]ethyl)-1H-indol-5-yl]cyclopropanecarboxamide

N-[2-methyl-3-(2-[N'-methyl-N'-([isoquinolin-7-yl]-methyl)amino]ethyl)-1H-indol-5-yl]cyclobutanecarboxamide

N-[2-methyl-3-(2-[N'-methyl-N'-([quinoxalin-2-yl]-methyl)amino]ethyl)-1H-indol-5-yl]cyclopentanecarboxamidehexanoate

N-[2-methyl-3-(2-[N'-methyl-N'-([quinazolin-5-yl]-methyl)amino]ethyl)-1H-indol-5-yl]cyclohexanecarboxamide

N-[2-methyl-3-(2-[N'-methyl-N'-([thiazol-2-yl]methyl)-amino]ethyl)-1H-indol-5-yl]cycloheptanecarboxamide

N-[2-methyl-3-(2-[N'-methyl-N'-([2-aminobenzothiazol-5-yl]methyl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamidetrifluoromethanesulfonate

N-[2-methyl-3-(2-[N'-methyl-N'-([oxazol-5-yl]methyl)-amino]ethyl)-1H-indol-5-yl]-3-iodobenzamide

N-[2-methyl-3-(2-[N'-methyl-N'-([6-nitrobenzoxazol-2-yl]methyl)amino]ethyl)-1H-indol-5-yl]-2-chlorobenzamidehydrobromide

N-[2-methyl-3-(2-[N'-methyl-N'-([1,4-benzodioxan-6-yl]-methyl)amino]ethyl)-1H-indol-5-yl]-2-chloropyridine-3-carboxamide

N-[2-isopropyl-3-(2-[N'-methyl-N'-([isoxazol-4-yl]-methyl)amino]ethyl)-1H-indol-5-yl]benzamide

N-[2-methyl-3-(2-[N'-methyl-N'-([benzisoxazol-3-yl]-methyl)amino]ethyl)-1H-indol-5-yl]thiophene-2-carboxamide

N-[2-methyl-3-(2-[N'-methyl-N'-([1,3,4-oxadiazol-2-yl]-methyl)amino]ethyl)-1H-indol-5-yl]furan-3-carboxamide

N-[2-methyl-3-(2-[N'-methyl-N'-([1,2,3-triazol-4-yl]-methyl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamidetosylate

N-[3-(2-[N'-methyl-N'-((4-bromothien-2-yl)methyl)amino]ethyl)-1H-indol-5-yl)]-4-fluorobenzamidehydrochloride

N-[2-ethyl-3-(2-[N'-ethyl-N'-((3-methylthiobenzofur-5-yl)ethyl)amino]ethyl)-1H-indol-5-yl]pyridine-2-carboxamide

N-[2-propyl-3-(2-[N'-isopropyl-N'-1-((isobenzofur-2-yl)prop-3-yl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

N-[2-methyl-3-(2-[N'-butyl-N'-(pyrrol-3-yl)methyl)-amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamidemaleate

N-[2-methyl-3-(2-[N'-methyl-N'-((5-cyanoimidazol-2-yl)methyl)amino]ethyl)-1H-indol-5-yl]-4-acetamidetrifluoroacetate

N-[2-methyl-3-(2-[N'-methyl-N'-((6-carboxamidopyrazin-2-yl)methyl)amino]ethyl)-1H-indol-5-yl]propanamide

N-[2-methyl-3-(2-[N'-methyl-N'-((5-nitropyrimidin-2-yl)methyl)amino]ethyl)-1H-indol-5-yl]-2-propanamide

N-[2-methyl-3-(2-[N'-methyl-N'-((5-dimethylaminopyridazin-3-yl)methyl)amino]ethyl)-1H-indol-5-yl]butyramidebenzoate

N-[2-methyl-3-(2-[N'-methyl-N'-((indazol-5-yl)methyl)amino]ethyl)-1H-indol-5-yl]pentanamide

N-[2-methyl-3-(2-[N'-methyl-N'-((quinolin-4-yl)methyl)-amino]ethyl)-1H-indol-5-yl]cyclopropanecarboxamide

N-[2-methyl-3-(2-[N'-methyl-N'-((isoquinolin-7-yl)methyl)amino]ethyl)-1H-indol-5-yl]cyclobutanecarboxamide

N-[2-methyl-3-(2-[N'-methyl-N'-((quinoxalin-2-yl)-methyl)amino]ethyl)-1H-indol-5-yl]cyclopentanecarboxamideacetate

N-[2-methyl-3-(2-[N'-methyl-N'-((quinazolin-5-yl)-methyl)amino]ethyl)-1H-indol-5-yl]cyclohexanecarboxamide

N-[2-methyl-3-(2-[N'-methyl-N'-((thiazol-2-yl)methyl)-amino]ethyl)-1H-indol-5-yl]cycloheptanecarboxamide

N-[2-methyl-3-(2-[N'-methyl-N'-((2-aminobenzothiazol-5-yl)methyl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamidetrifluoromethanesulfonate

N-(2-methyl-3-(2-[N'-methyl-N'-(2-[pyridin-4-yl]-ethyl)amino]ethyl)-1H-indol-5-yl]-N"-ethylurea

N-[2-methyl-3-(2-[N'-methyl-N'-s-butylamino]ethyl)-1H-indol-5-yl]-N"-isopropylurea

N-[2-methyl-3-(2-[N'-methyl-N'-(2-[pyridin-4-yl]-ethyl)amino]ethyl)-1H-indol-5-yl]-N"-[(3-methoxy)phenyl]ureamalonate

N-[3-(2-(N'-(2-[1-isopropylpyrazol-4-yl]ethyl)amino]ethyl)-1H-indol-5-yl]-N"-[(2-ethoxy)phenyl]-ureamandelate

N-[3-(2-[N'-methyl-N'-([4-bromothien-2-yl]-methyl)amino]ethyl)-1H-indol-5-yl]-N"-[(4-isopropoxy)phenyl]-ureahydrochloride

N-[2-ethyl-3-(2-[N'-(2-[3-methylthiobenzofur-5-yl]ethyl)amino]ethyl)-1H-indol-5-yl]-N"-[2,3-dibromophenyl]-urea

N-[2-propyl-3-(2-[N'-isopropyl-N'-(3-[isobenzofur-2-yl]-propyl)amino]ethyl)-1H-indol-5-yl]-N"-[(2-bromo-3-iodo)phenyl]urea

N-[2-methyl-3-(2-[N'-butyl-N'-([pyrrol-3-yl]methyl)-amino]ethyl)-1H-indol-5-yl]-N"-benzylureamaleate

N-[2-methyl-3-(2-[N'-methyl-N'-([5-cyanoimidazol-2-yl]-methyl)amino]ethyl)-1H-indol-5-yl]-N"-phenethylureatrifluoroacetate

N-[2-methyl-3-(2-[N'-methyl-N'-([6-carboxamidopyrazin-2-yl]methyl)amino]ethyl)-1H-indol-5-yl]-N"-[4-phenbutyl]urea

N-[2-methyl-3-(2-[N'-methyl-N'-([5-nitropyrimidin-2-yl]-methyl)amino]ethyl)-1H-indol-5-yl]-N"-[(2-trifluoromethyl)-phenyl]urea

N-[2-methyl-3-(2-[N'-methyl-N'-([5-dimethylaminopyridazin-3-yl]methyl)amino]ethyl)-1H-indol-5-yl]-N"-[(3-phenyl)-phenyl]ureabenzoate

1-{[2-methyl-3-(2-[N'-methyl-N'-([indazol-5-yl]methyl)-amino]ethyl)-1H-indol-5-yl]carbonyl}pyrrolidine

1-{[2-methyl-3-(2-[N'-methyl-N'-([quinolin-4-yl]methyl)-amino]ethyl)-1H-indol-5-yl]carbonyl}piperidine

1-{[2-methyl-3-(2-[N'-methyl-N'-([isoquinolin-7-yl]-methyl)amino]ethyl)-1H-indol-5-yl]carbonyl}piperazine

1-{[2-methyl-3-(2-[N'-methyl-N'-([quinoxalin-2-yl]-methyl)amino]ethyl)-1H-indol-5-yl]carbonyl}-4-methylpiperazinehexanoate

1-{[2-isopropyl-3-(2-[N'-methyl-N'-([quinazolin-5-yl]-methyl)amino]ethyl)-1H-indol-5-yl]carbonyl}-4-phenylpiperazine

1-{[3-(2-[N'-([thiazol-2-yl]methyl)amino]ethyl)-1H-indol-5-yl]carbonyl}-4-benzylpiperazine

1-{[2-methyl-3-(2-[N'-([2-aminobenzothiazol-5-yl]-methyl)amino]ethyl)-1H-indol-5-yl]carbonyl}-4-(2,4-dichiorophenyl)piperazinetrifluoromethanesulfonate

1-{[3-(2-[N'-methyl-N'-([oxazol-5-yl]methyl)-amino]ethyl)-1H-indol-5-yl]carbonyl}morpholine

1-{[2-methyl-3-(2-[N'-methyl-N'-([6-nitrobenzoxazol-2-yl]methyl)amino]ethyl)-1H-indol-5-yl]carbonyl}thiomorpholinehydrobromide

N-[2-methyl-3-(2-[N'-methyl-N'-(2-[pyridin-4-yl]-ethyl)amino]ethyl)-1H-indol-5-yl]-N"-ethylthiourea

N-[2-methyl-3-(2-[N'-methyl-N'-s-butylamino]ethyl)-1H-indol-5-yl]-N"-isopropylthiourea

N-[2-methyl-3-(2-[N'-methyl-N'-(2-[pyridin-4-yl]-ethyl)amino]ethyl)-1H-indol-5-yl]-N"-[(3-methoxy)phenyl]thioureamalonate

N-[2-methyl-3-(2-[N'-methyl-N'-(2-[1-isopropylpyrazol-4-yl]ethyl)amino]ethyl)-1H-indol-5-yl]-N"-[(2-ethoxy)phenyl]-thioureamandelate

N-[2-phenyl-3-(2-[N'-methyl-N'-([4-bromothien-2-yl]-methyl)amino]ethyl)-1H-indol-5-yl]-N"-[(4-isopropoxy)phenyl]-thioureahydrochloride

N-[2-ethyl-3-(2-[N'-ethyl-N'-(2-[3-methylthiobenzofur-5-yl]ethyl)amino]ethyl)-1H-indol-5-yl]-N"-[2,3-dibromophenyl]-thiourea

N-[2-propyl-3-(2-[N'-isopropyl-N'-(3-[isobenzofur-2-yl]-propyl)amino]ethyl)-1H-indol-5-yl]-N"-[(2-bromo-3-iodo)phenyl]thiourea

N-[3-(2-[N'-([pyrrol-3-yl]methyl)amino]ethyl)-1H-indol-5-yl]-N"-benzylthioureamaleate

N-[3-(2-[N'-methyl-N'-([5-cyanoimidazol-2-yl]methyl)-amino]ethyl)-1H-indol-5-yl]-N"-phenethylthioureatrifluoroacetate

N-[2-methyl-3-(2-[N'-([6-carboxamidopyrazin-2-yl]-methyl)amino]ethyl)-1H-indol-5-yl]-N"-[4-phenbutyl]thiourea

N-[2-methyl-3-(2-[N'-methyl-N'-([5-nitropyrimidin-2-yl]-methyl)amino]ethyl)-1H-indol-5-yl]-N"-[(2-trifluoromethyl)-phenyl]thiourea

N-[2-methyl-3-(2-[N'-methyl-N'-([5-dimethylaminopyridazin-3-yl]methyl)amino]ethyl)-1H-indol-5-yl]-N"-[(3-phenyl)-phenyl]thioureabenzoate

1-{N-[2-methyl-3-(2-[N'-methyl-N'-([indazol-5-yl]-methyl)amino]ethyl)-1H-indol-5-yl]aminothiocarbonyl}pyrrolidine

1-{N-[2-methyl-3-(2-[N'-methyl-N'-([quinolin-4-yl]-methyl)amino]ethyl)-1H-indol-5-yl]aminothiocarbonyl}piperidine

1-{N-[2-methyl-3-(2-[N'-methyl-N'-([isoquinolin-7-yl]-methyl)amino]ethyl)-1H-indol-5-yl]aminothiocarbonyl}piperazine

1-{N-[2-methyl-3-(2-[N'-([quinoxalin-2-yl]methyl)-amino]ethyl)-1H-indol-5-yl]aminothiocarbonyl}-4-methylpiperazinehexanoate

1-{N-[2-methyl-3-(2-[N'-methyl-N'-([quinazolin-5-yl]-methyl)amino]ethyl)-1H-indol-5-yl]aminothiocarbonyl}-4-phenylpiperazine

1-{N-[2-methyl-3-(2-[N'-methyl-N'-([thiazol-2-yl]-methyl)amino]ethyl)-1H-indol-5-yl]aminothiocarbonyl}-4-benzylpiperazine

1-{N-[2-methyl-3-(2-[N'-methyl-N'-([2-aminobenzothiazol-5-yl]methyl)amino]ethyl)-1H-indol-5-yl]aminothiocarbonyl}-4-(2,4-dichlorophenyl)piperazinetrifluoromethanesulfonate

1-{N-[2-methyl-3-(2-[N'-methyl-N'-([oxazol-5-yl]methyl)-amino]ethyl)-1H-indol-5-yl]aminothiocarbonyl}morpholine

1-{N-[2-methyl-3-(2-[N'-methyl-N'-([6-nitrobenzoxazol-2-yl]methyl)amino]ethyl)-1H-indol-5-yl]aminothiocarbonyl}thiomorpholinehydrobromide

N-[2-methyl-3-(2-[N'-([benzisoxazol-3-yl]methyl)-amino]ethyl)-1H-indol-5-yl]thiophene-2-carboxamide

N-[2-methyl-3-(2-[N'-([1,3,4-oxadiazol-2-yl]methyl)-amino]ethyl)-1H-indol-5-yl]furan-³-carboxamide

N-[2-methyl-3-(2-[N'-([1,2,3-triazol-4-yl]methyl)-amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamidetosylate

N-[2-phenyl-3-(2-[N'-((4-bromothien-2-yl)methyl)amino]ethyl)-1H-indol-5-yl)]-4-fluorobenzamidehydrochloride

N-[2-ethyl-3-(2-[N'-((3-methylthiobenzofur-5-yl)ethyl)amino]ethyl)-1H-indol-5-yl]pyridine-2-carboxamide

N-[2-propyl-3-(2-[N'-1-((isobenzofur-2-yl)prop-3-yl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

N-[2-methyl-3-(2-[N'-(pyrrol-3-yl)methyl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamidemaleate

N-[2-methyl-3-(2-[N'-((5-cyanoimidazol-2-yl)methyl)amino]ethyl)-1H-indol-5-yl]-4-acetamidetrifluoroacetate

N-[2-methyl-3-(2-[N'-((6-carboxaridopyrazin-2-yl)methyl)amino]ethyl)-1H-indol-5-yl]propanamide

5-(N,N-dibutylaminosulfonyl)amino-2-methyl-3-(2-[N'-methyl-N'-((5-nitropyrimidin-2-yl)methyl)amino]ethyl)-1H-indole

5-((N-isopropyl-N-butylamino)sulfonyl)amino-2-methyl-3-(2-[N'-methyl-N-((5-dimethylaminopyridazin-3-yl)methyl)-amino]ethyl)-1H-indolebenzoate

5-(dimethylaminosulfonyl)amino-2-methyl-3-(2-[N'-methyl-N'-((indazol-5-yl)methyl)amino]ethyl)-1H-indole

N-[2-methyl-3-(2-[N'-methyl-N-((quinolin-4-yl)methyl)-amino]ethyl)-1H-indol-5-yl]-4-chlorophenylsulfonamide

N-[2-methyl-3-(2-[N'-methyl-N'-((isoquinolin-7-yl)methyl)amino]ethyl)-1H-indol-5-yl]phenylsulfonamide

N-[2-methyl-3-(2-[N'-methyl-N'-((quinoxalin-2-yl)-methyl)amino]ethyl)-1H-indol-5-yl]butanesulfonamideacetate

N-[2-methyl-3-(2-[N-methyl-N'-((quinazolin-5-yl)-methyl)amino]ethyl)-1H-indol-5-yl]isopropanesulfonamide

N-[2-methyl-3-(2-[N'-methyl-N'-((thiazol-2-yl)methyl)-amino]ethyl)-1H-indol-5-yl]propanesulfonamide

N-[2-methyl-3-(2-[N'-((2-aminobenzothiazol-5-yl)methyl)amino]ethyl)-1H-indol-5-yl]ethanesulfonamidetrifluoromethanesulfonate

5-isopropoxycarbonylamino-2-methyl-3-(2-[N'-methyl-N'-(2-[1-isopropylpyrazol-4-yl]ethyl)amino]ethyl)-1H-indolemandelate

5-methoxycarbonylamino-(2-[N'-methyl-N'-([4-bromothien-2-yl]methyl)amino]ethyl)-1H-indolehydrochloride

5-(tert-butoxycarbonyl)amino-2-ethyl-3-(2-[N'-ethyl-N'-(2-[3-methylthiobenzofur-5-yl]ethyl)amino]ethyl)-1H-indole

5-(1-penten-5-yloxy)carbonylamino-2-propyl-3-(2-[N'-isopropyl-N'-(3-[isobenzofur-2-yl]propyl)amino]ethyl)-1H-indole

5-(1-buten-4-yloxy)carbonylamino-2-methyl-3-(2-[N'-butyl-N'-([pyrrol-3-yl]methyl)amino]ethyl)-1H-indolemaleate

5-(4-hexen-6-yloxy)carbonylamino-3-(2-[N'-methyl-N'-([5-cyanoimidazol-2-yl]methyl)amino]ethyl)-1H-indoletrifluoroacetate

5-(2-chlorophenoxy)carbonylamino-2-methyl-3-(2-[N'-([6-carboxamidopyrazin-2-yl]methyl)amino]ethyl)-1H-indole

5-(3-bromophenoxy)carbonylamino-3-(2-[N'-([5-nitropyrimidin-2-yl]methyl)amino]ethyl)-1H-indole

5-(3-methoxyphenoxy)carbonylamino-2-methyl-3-(2-[N'-methyl-N'-([5-dimethylaminopyridazin-3-yl]methyl)-amino]ethyl)-1H-indolebenzoate

5-cyclopropoxycarbonylamino-2-methyl-3-(2-[N'-methyl-N'-([indazol-5-yl]methyl)amino]ethyl)-1H-indole

5-cyclohexyloxycarbonylamino-2-methyl-3-(2-[N'-methyl-N'-([quinolin-4-yl]methyl)amino]ethyl)-1H-indole

5-cyclooctyloxycarbonylamino-2-methyl-3-(2-[N'-methyl-N'-([isoquinolin-7-yl]methyl)amino]ethyl)-1H-indole

5-(butoxymethoxy)carbonylamino-2-methyl-3-(2-[N'-methyl-N'-([quinoxalin-2-yl]methyl)amino]ethyl)-1H-indolehexanoate

5-(ethoxypropoxy)carbonylamino-N-[2-methyl-3-(2-[N'-methyl-N'-([quinazolin-5-yl]methyl)amino]ethyl)-1H-indole

The synthetic methodology required to prepare the compounds of theinvention is well known to those skilled in the art. An appropriatenitrobenzene is hydrogenated to give the corresponding aniline. Thisaniline is then diazotized and reduced to give the correspondinghydrazine which is then combined with an appropriate ketone underFischer indole cyclization conditions to give the compounds of thepresent invention. This chemistry is illustrated in Synthetic Scheme Iwhere X is R⁴ C(O)NH--, R⁵ R⁶ NC(Y)NH--, or R⁸ SO₂ NH-- and R¹, R², R³,R⁴, R⁵, R⁶, R⁸ and Y are as described supra. ##STR3##

The 4-nitrobenzenes (i) are converted to the corresponding4-aminobenzenes (ii) by catalytic hydrogenation. These hydrogenationsare performed using a precious metal catalyst, such as platinum oxide orplatinum or palladium on a support such as carbon. The hydrogenationsolvent may consist of a lower alkanol, such as methanol or ethanol,tetrahydrofuran, or a mixed solvent system of tetrahydrofuran and ethylacetate. The hydrogenation may be performed at an initial hydrogenpressure of 20-80 p.s.i., preferably from 50-60 p.s.i., at 0-60° C.,preferably at ambient temperature to 40° C., for 1 hour to 3 days.Additional charges of hydrogen may be required to drive the reaction tocompletion depending on the specific substrate. The 4-aminobenzenes (ii)prepared in this manner are isolated by removal of the catalyst byfiltration followed by concentration of the reaction solvent underreduced pressure. The product recovered may be used directly in asubsequent step or further purified by chromatography, or byrecrystallization from a suitable solvent.

The 4-aminobenzenes (ii) are then diazotized by suspension inconcentrated hydrochloric acid cooled to about 0° C. To this cooledmixture is then added an aqueous solution of sodium or potassium nitriteat such a rate as to maintain the temperature of the reaction mixture ator below 5° C. The reaction is stirred at about 0° C. for from about 10minutes to about an hour. The resulting diazonium salt mixture isreduced directly by dropwise addition to a solution of stannous chloridein concentrated hydrochloric acid at such a rate as to maintain thetemperature of the reaction mixture at about 0° C. A solid forms whichis recovered by filtration. The solid is partitioned between an aqueousbase, such as sodium hydroxide, and a suitable water immiscible solvent,such as diethyl ether or ethyl acetate. The hydrazine (iii) is isolatedby separating the water immiscible phase, drying over an appropriatedessicant, such as sodium or magnesium sulfate, and removing the solventunder reduced pressure. The product recovered may be used directly in asubsequent step or further purified by chromatography, or byrecrystallization from a suitable solvent.

The hydrazines (iii) are then reacted with an appropriate aminoketone(iv) under standard Fischer indolization conditions as described inRobinson, The Fischer Indole Synthesis, Wiley, New York, 1983; Hamel, etal., Journal of Organic Chemistry, 59, 6372 (1994); and Russell, et al.,Organic Preparations and Procedures International, 17, 391 (1985), toprovide the compounds of the present invention.

The nitrobenzenes required for the synthesis of the compounds of thepresent invention may be prepared by reacting suitable electrophileswith 4-nitroaniline to provide the corresponding ureas, thioureas,sulfonamides and carboxamides. This chemistry is illustrated inSynthetic Scheme II where R⁴, R⁵, R⁶, and R⁸ are as described supra.##STR4##

To prepare compounds of the invention where X is R⁸ SO₂ NH--, a solutionof 4-nitroaniline in a suitable solvent, such as tetrahydrofuran,dioxane, diethyl ether or dimethylformamide, at a temperature from aboutambient to about 0° C., is reacted with a commercially available R⁸-sulfonyl halide or R⁸ -sulfonic anhydride in the presence of a suitablebase such as pyridine or triethylamine. The resultant sulfonamide may beisolated by dilution of the reaction mixture with water, adjustment ofpH, and extraction with a water immiscible solvent such asdichloromethane. The product may be used for further reaction asrecovered, or may be purified by chromatography, or by recrystallizationfrom a suitable solvent.

Compounds of the invention where X is --NHC(Y)NR⁵ R⁶ are prepared bytreating a solution of nitroaniline in a suitable solvent, such aschloroform or dichloromethane, with an appropriate isocyanate,isothiocyanate, carbamoyl chloride or carbamoyl bromide. Appropriatecarbamoyl chlorides are available by treating an amine of formula HNR⁵R⁶ with phosgene. When a carbamoyl chloride or carbamoyl bromide isused, the reactions are performed in the presence of a suitable base.Suitable bases include amines typically used as acid scavengers, such aspyridine or triethylamine, or commercially available polymer bound basessuch as polyvinylpyridine. If necessary, an excess of the isocyanate,isothiocyanate, carbamoyl chloride or carbamoyl bromide is employed toensure complete reaction of the starting amine. The reactions areperformed at about ambient to about 80° C., for from about three hoursto about three days. Typically, the product may be isolated by washingthe reaction mixture with water and concentrating the remaining organicsunder reduced pressure. When an excess of isocyanate, isothiocyanate,carbamoyl chloride or carbamoyl bromide has been used, however, apolymer bound primary or secondary amine, such as an aminomethylatedpolystyrene, may be conveniently added to react with the excess reagent.Isolation of products from reactions where a polymer bound reagent hasbeen used is greatly simplified, requiring only filtration of thereaction mixture and then concentration of the filtrate under reducedpressure. The product from these reactions may be purifiedchromatographically or recrystallized from a suitable solvent ifdesired. The skilled artisan will appreciate that compounds of theinvention which are ureas may be converted into the correspondingthiourea by treatment with[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide](Lawesson's Reagent) or phosphorus pentasulfide.

Compounds of the invention where X is R⁴ C(O)NH-- are prepared bytreating 4-nitroaniline with an appropriate carboxylic acid chloride,bromide or anhydride, optionally in the presence of an acylationcatalyst such as dimethylaminopyridine, in the presence of a suitablebase. Suitable bases include amines typically used as acid scavengers,such as pyridine or triethylamine, or commercially available polymerbound bases such as polyvinylpyridine. When an excess of the carboxylicacid chloride, bromide or anhydride is necessary to ensure completereaction of the amine, a polymer bound primary or secondary amine, suchas an aminomethylated polystyrene, may be conveniently added to reactwith the excess reagent. Isolation of products from reactions where apolymer bound reagent has been used is greatly simplified, requiringonly filtration of the reaction mixture to remove the polymer boundconstituents, and then concentration of the filtrate under reducedpressure to isolate the desired product. The product from thesereactions may be purified chromatographically or recrystallized from asuitable solvent if desired.

Alternatively, the 4-nitroaniline is reacted with an appropriatecarboxylic acid in the presence of a typical peptide coupling reagentsuch as N,N'-carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide(DCC) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC). Polymer supported forms of carbodiimide peptide coupling reagentsare useful for the preparation of compounds of the present invention. Apolymer supported form of EDC, for example, has been described(Tetrahedron Letters, 34(48), 7685 (1993)). Additionally, a newcarbodiimide coupling reagent,1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (PEPC), and itscorresponding polymer supported forms have been discovered and are veryuseful for the preparation of the compounds of the present invention.

Polymers suitable for use in making a polymer supported coupling reagentare either commercially available or may be prepared by methods wellknown to the artisan skilled in the polymer arts. A suitable polymermust possess pendant sidechains bearing moieties reactive with theterminal amine of the carbodiimide. Such reactive moieties includechloro, bromo, iodo and methanesulfonyl. Preferably, the reactive moietyis a chloromethyl group. Additionally, the polymer's backbone must beinert to both the carbodiimide and reaction conditions under which theultimate polymer bound coupling reagents will be used.

Certain hydroxymethylated resins may be converted into chloromethylatedresins useful for the preparation of polymer supported couplingreagents. Examples of these hydroxylated resins include the4-hydroxymethyl-phenylacetamidomethyl resin (Pam Resin) and4-benzyloxybenzyl alcohol resin (Wang Resin) available from AdvancedChemtech of Louisville, Ky. (see Advanced Chemtech 1993-1994 catalog,page 115). The hydroxymethyl groups of these resins may be convertedinto the desired chloromethyl groups by any of a number of methods wellknown to the skilled artisan.

Preferred resins are the chloromethylated styrene/divinylbenzene resinsbecause of their ready commercial availability. As the name suggests,these resins are already chloromethylated and require no chemicalmodification prior to use. These resins are commercially known asMerrifield's resins and are available from Aldrich Chemical Company ofMilwaukee, Wis. (see Aldrich 1994-1995 catalog, page 899).

Methods for the preparation of PEPC and its polymer supported forms areoutlined in the following scheme. ##STR5##

Briefly, PEPC is prepared by first reacting ethyl isocyanate with1-(3-aminopropyl)pyrrolidine. The resulting urea is treated with4-toluenesulfonyl chloride to provide PEPC. The polymer supported formis prepared by reaction of PEPC with an appropriate resin under standardconditions to give the desired reagent.

The carboxylic acid coupling reactions employing these reagents areperformed at about ambient to about 45° C., for from about three hoursto about three days. Typically, the product may be isolated by washingthe reaction with water and concentrating the remaining organics underreduced pressure. As discussed supra, isolation of products fromreactions where a polymer bound reagent has been used is greatlysimplified, requiring only filtration of the reaction mixture and thenconcentration of the filtrate under reduced pressure. TheN-(4-nitro)phenylamides from these reactions may be used directly in asubsequent step or first purified chromatographically or recrystallizedfrom a suitable solvent prior to further reaction if desired.

The aminoketones required for the Fischer indolization step areavailable by methods well known to the skilled artisan. One method is toreact an appropriate haloketone, optionally protected as thecorresponding ketal, with an appropriate amine or phthalimidate saltunder standard alkylating conditions as described in Synthetic SchemeIII, where halo is chloro, bromo or iodo and R¹, R² and R³ are asdefined supra. ##STR6## The haloketone and an appropriate amine arecombined in a suitable solvent, such as acetonitrile, dichloromethane,acetone or dimethylformamide, in the presence of a suitable base, suchas potassium or sodium carbonate. The skilled artisan will appreciatethat when the haloketone is reacted with a phthalimidate salt, however,no additional base is required. The resulting mixture is heated to atemperature from about 40° C. to about 120° C. until all reactants areconsumed. These reactions typically require about 2 hours to about 3days to reach completion. The desired aminoketones may be isolated byfiltering the reaction mixture to remove any solids which have formed,and concentrating the reaction mixture under reduced pressure.Alternatively, the reaction mixture may be partitioned between water anda water immiscible solvent such as dichloromethane. The water immisciblephase is then concentrated under reduced pressure to provide the desiredcompound. The aminoketones isolated in this manner may be used directlyin a subsequent step or purified by distillation, chromatography, orcrystallization from a suitable solvent if desired.

The skilled artisan will appreciate that certain of the compounds of thepresent invention, while useful as 5-HT_(1F) agonists in their ownright, are also useful intermediates for the preparation of othercompounds of the present invention. The amide moiety, for example, maybe hydrolyzed to provide the corresponding5-amino-3-(2-aminoethyl)-1H-indole. This hydrolysis may be performed byheating a mixture of the amide and 6N hydrochloric acid at reflux forabout 4 hours to about 2 days. After cooling, the aqueous phase isextracted with a water immiscible solvent, such as toluene, benzene orhexane. This water immiscible phase is discarded and then the remainingaqueous phase is treated with a base such as sodium, potassium orammonium hydroxide, until the solution has reached a pH of about 11 or12. The aqueous phase is then extracted with a water immiscible solventlike dichloromethane. These organic extracts are concentrated underreduced pressure to give the corresponding5-amino-3-(2-aminoethyl)-1H-indole which may be reacted directly orfirst purified by chromatography or recrystallization from anappropriate solvent.

Compounds of the invention where X is --NHC(O)OR¹² are prepared byreacting the 5-amino-3-(2-aminoethyl)-1H-indole with an appropriatelysubstituted chloroformate in the presence of a suitable amine under theconditions described for Synthetic Scheme II. Likewise, the skilledartisan will appreciate that the amides, ureas, thioureas, andsulfonamides of the invention may be prepared by reacting the5-amino-3-(2-aminoethyl)-1H-indole with an appropriate electrophile asdescribed supra.

Alternatively, the 2-substituted-5-amino-3-(2-aminoethyl)-1H-indoles maybe prepared by the reaction of 4-nitrophenylhydrazine with anappropriate aminoketone (Synthetic Scheme I) under the Fischerindolization conditions described by Robinson, The Fischer IndoleSynthesis, Wiley, N.Y., 1983; Hamel, et al., Journal of OrganicChemistry, 59, 6372 (1994); and Russell, et al., Organic Preparationsand Procedures International, 17, 391 (1985). The resulting5-nitroindole may be hydrogenated to give the same2-substituted-5-amino-3-(2-aminoethyl)-1H-indoles prepared by thehydrolysis described supra.

Additionally, when compounds of the present invention where R² is benzylor 1-phenylethyl are subjected to the hydrogenation conditions describedsupra, the R² substituent is removed by hydrogenolysis to give thecorresponding secondary amines (III). These secondary amines may then bealkylated with an appropriate alkylating agent under the alkylationconditions described supra, or they may be subjected to reductivealkylation conditions in the presence of an appropriate aldehyde, toprovide additional compounds of the invention. Furthermore, thephthalimides described supra may be treated with hydrazine to providethe primary amines (IV). These primary amines may be treated subjectedto sequential reductive alkylations to provide the compounds of thepresent invention. This chemistry is illustrated in Synthetic Scheme IVwhere R^(2') -CHO represents an aldehyde which, after undergoing thereductive alkylation reaction provides the moiety R², and R¹, R², R³ andX are as defined supra. ##STR7##

The reductive alkylation may be performed by combining an appropriatealdehyde, for example R^(2') -CHO, with the secondary amine (III) orprimary amine (IV) in a suitable solvent. Suitable solvents includetetrahydrofuran, dichioromethane, and the lower alkanols such asmethanol, ethanol or isopropanol. The preferred solvents for thereductive alkylation include methanol and dichloromethane. The aldehydeand amine are typically combined in the presence of an acid, such asacetic acid or hydrogen chloride, and a hydride reducing agent. Suitablehydride reducing agents include sodium borohydride, sodiumcyanoborohydride or sodium triacetoxyborohydride. Preferred hydridereducing agents include sodium cyanoborohydride or sodiumtriacetoxyborohydride. The combined reagents are allowed to react at atemperature of from about ambient to the reflux temperature of thesolvent. The reaction time is typically from about 3 to about 24 hours.The compounds of the invention may then be isolated and purified bystandard extractive workups. The compounds may be further purified bychromatography or crystallization from suitable solvents if desired.

The skilled artisan will appreciate that reductive alkylations of theprimary amine (IV) may be performed sequentially. One equivalent of afirst aldehyde is used to prepare the corresponding secondary amineunder standard reductive alkylation procedures. This secondary amine maybe isolated if desired or treated directly with a second aldehyde underthe reductive alkylation conditions described supra. When R¹ and R² areto be the same, the primary amine may be exhaustively alkylated ifdesired.

The skilled artisan will also appreciate that, as an alternative to thereductive alkylation conditions described supra, the aldehyde and aminemay be combined in a suitable solvent in the presence of acid. Theresulting imine may then be reduced in a separate step by addition of asuitable hydride reducing agent, or by subjecting the reaction mixtureto hydrogenation conditions using standard precious metal catalysts. Theuse of hydrogenation conditions is limited to those compounds of theinvention which are stable to the reaction conditions. The skilledartisan will also appreciate that while the reductive alkylationprocedures described supra describe the use of aldehydes, ketones mayalso be used to prepare other compounds of the invention.

The leaving group (LG) of the alkylating agents may be chloro, bromo,iodo, methanesulfonyloxy, trifluoromethanesulfonyloxy,2,2,2-trifluoroethanesulfonyloxy, benzenesulfonyloxy,p-bromobenzenesulfonyloxy, p-nitrobenzenesulfonyloxy orp-toluenesulfonyloxy, all of which are useful for the preparation ofcompounds of this invention. The specific alkylating agent employed isdetermined by its commercial availability or a convenient synthesis fromcommercially available starting materials. The preferred alkylatingagents for synthesis of compounds of this invention are those where theleaving group is chloro, bromo or methanesulfonyloxy.

Alkylating agents required to prepare compounds where R² is aryl-(C₁ -C₃alkylene) or heteroaryl-(C₁ -C₃ alkylene), if not commerciallyavailable, are prepared from the corresponding alcohol by standardmethods. When the preferred leaving group of the alkylating group ischloro, the alcohol may be treated with neat thionyl chloride at ambienttemperature. When it is preferred that the leaving group for thesealkylating agents is methanesulfonyloxy, they may be prepared from thecorresponding alcohols as described in Synthetic Scheme V where Ar isphenyl, substituted phenyl, or a heterocycle as defined supra, and n is1-3. ##STR8##

The alcohol is dissolved in a suitable anhydrous solvent such astetrahydrofuran, diethyl ether, p-dioxane or acetonitrile which containsthe base. The base must be sufficiently basic to neutralize the acidgenerated during the progress of the reaction but not so basic as todeprotonate other sites in the substrate giving rise to other products.Additionally, the base must not compete to any great extent with thesubstrate for the sulfonating reagent and must have sufficientsolubility in the reaction solvent. Bases typically used in thesereactions are tertiary amines such as pyridine, triethylamine orN-methylmorpholine. To the reaction mixture is then added thesulfonating reagent with cooling. The sulfonating reagent may be amethanesulfonyl halide such as the fluoride or chloride, ormethanesulfonic anhydride. The reaction mixture is allowed to react from1 hour to 24 hours at ambient temperature. The product is isolated byconcentrating the reaction mixture under reduced pressure followed bypartitioning the residue between water and an appropriate organicsolvent such as dichloromethane, ethylene chloride, chloroform or carbontetrachloride. The isolated product is used directly in the alkylationstep.

The alcohols required for the synthesis of compounds of this inventionwhere R² is aryl-(C₁ -C₃ alkylene) or heteroaryl-(C₁ -C₃ alkylene) areeither commercially available or may be prepared by employing wellestablished synthetic methodology. A general scheme for the synthesis ofa number of these required alcohols is described in Synthetic Scheme VI,where Ar is pyridinyl or phenyl and n is 1-3. ##STR9## An appropriatecarboxylic acid is reduced to the corresponding alcohol in diethyl etheror, preferably, tetrahydrofuran. The solution is added to a suspensionof an appropriate hydride reducing agent, preferably lithium aluminumhydride, in the same solvent at reduced temperature, typically about 0°C. Once the addition is complete the mixture is allowed to warm toambient and is stirred at ambient to reflux until the reduction iscomplete. The alcohol recovered may typically be used without furtherpurification.

The starting alcohols required for the preparation of those compounds ofthe invention where R² is heteroaryl-(C₁ -C₃ alkylene) and theheteroaryl moiety is pyrazol-4-yl, may be prepared by the general schemedescribed in Synthetic Scheme VI. ##STR10##

4,5-Dihydrofuran is treated with triethylorthoformate in the presence ofa Lewis acid, preferably boron trifluoride diethyl etherate, for from 1to 4 days at ambient temperature. After treating the reaction mixturewith an anhydrous base such as potassium carbonate, the intermediatediacetal is distilled from the reaction mixture. This diacetal is nowtreated with an appropriate hydrazine in aqueous acid at reflux for 4-24hours. The product is recovered by treatment of the reaction mixturewith base and extraction of the base into methylene chloride. Thealcohol so recovered is suitable for use without further purification.Where Q is H, the resulting alcohol can be further modified, if desired,by direct alkylation of one of the pyrazole nitrogens as described inSynthetic Scheme VII. ##STR11## The alkylating agent is a C₁ -C₃ alkylhalide, preferably the bromide or iodide. The reaction is performedunder the alkylation conditions described supra.

Alternatively, the compounds of the present invention may be preparedfrom the appropriate 2-substituted-5-nitroindoles. These startingindoles may be prepared by reaction of 4-nitrophenylhydrazine and aketone of formula R³ -C(O)CH₃, where R³ is as defined supra, underFischer indolization conditions as described by Robinson, The FischerIndole Synthesis, Wiley, N.Y., 1983; Hamel, et al., Journal of OrganicChemistry, 59, 6372 (1994); and Russell, et al., Organic Preparationsand Procedures International, 17, 391 (1985). The 3-(2-aminoethyl)functionality may then be introduced by chemistry described by Larsen etal. (U.S. Pat. No. 3,472,870 (Oct. 14, 1969)), Smythies (U.S. Pat. No.3,915,990 (Oct. 28, 1975)), and Stanley et al. (U.S. Pat. No. 4,803,218(Feb. 7, 1989)), herein incorporated by reference.

The following preparations and examples further illustrate the synthesisof the compounds of this invention, and are not intended to limit thescope of the invention in any way. The compounds described below wereidentified by various standard analytical techniques as stated in theindividual preparations and examples.

The aminoketones required for the synthesis of the compounds of theinvention are available by the procedures described in Preparations Iand II.

Preparation I N,N-dimethyl-5-amino-2-pentanone

A mixture of 21.77 gm (180.5 mMol) 5-chloro-2-pentanone, 13.40 gm (164.3mMol) dimethylamine hydrochloride and 50.0 gm (361.8 mMol) potassiumcarbonate in 150 mL acetonitrile was stirred at room temperature for 2days and then at reflux for 2 hours. The reaction mixture was thencooled to room temperature and partitioned between water anddichloromethane. The phases were separated and the aqueous phase againextracted with dichloromethane. All organic phases were combined, driedover sodium sulfate and concentrated under reduced pressure. The residuewas subjected to silica gel chromatography, eluting with dichloromethanecontaining 10% methanol and 1% ammonium hydroxide. Fractions shown tocontain product were combined and concentrated under reduced pressure.The desired product was then isolated by distillation.

Preparation II N-methyl-N-((S)-1-phenylethyl)-5-amino-2-pentanone

A mixture of 5.85 mL (38.87 mMol) 5-chloro-2-pentanone ethylene glycolketal, 5.0 gm (37.0 mMol) N-methyl-(S)-1-phenylethylamine, 6.14 gm (37.0mMol) potassium iodide and 15.33 gm (110.9 mMol) potassium carbonate in100 mL acetonitrile was stirred at room temperature for 2 days. Thereaction mixture was then filtered and the filtrate concentrated underreduced pressure. The residue was dissolved in 50 mL acetone to whichwas added 50 mL 2N hydrochloric acid. The resulting solution was stirredat room temperature for 3 hours and was then concentrated to half volumeunder reduced pressure. The residue was extracted diethyl ether (2×50mL) and the remaining aqueous solution was treated with 5N sodiumhydroxide until the pH of the solution was about 13. This aqueous phasewas now extracted with dichloromethane (3×60 mL). The organic phaseswere combined, dried over sodium sulfate and concentrated under reducedpressure. The residue was subjected to silica gel chromatography,eluting with 40% ethyl acetated in hexane. Fractions shown to containproduct were combined and concentrated under reduced pressure to give7.11 gm (88%) of the desired compound.

Preparation III N-(4-fluorobenzoyl)-4-aminophenylhydrazine

Acylation of 4-nitroaniline

To a stirred suspension of 19.83 gm (143.56 mMol) 4-nitroaniline in 150mL dichloromethane and 12.9 mL (159.5 mMol) pyridine at 0° C. wereslowly added 24.5 gm (154.8 mMol) 4-fluorobenzoyl chloride. The reactionmixture was then stirred for 15 minutes at 0° C., at which time thereaction mixture became homogeneous, and then for an hour at roomtemperature. To this mixture were then added 100 mL water and the solidwhich formed was collected by filtration. The filter cake was washedwith hexane (80 mL) followed by water (100 mL) and it was then driedunder vacuum at 60° C. to give 34.1 gm (91%)N-(4-fluorobenzoyl)-4-nitroaniline.

m.p.=117-118° C.; MS(FD): m/e=260 (M⁺)

Catalytic Hydrogenation of Nitro Group

A mixture of 32.25 gm (124 mMol) N-(4-fluorobenzoyl)-4-nitroaniline and3.2 gm platinum on carbon in 500 mL tetrahydrofuran was hydrogenated atroom temperature for 18 hours with an initial pressure of 60 p.s.i. Thereaction mixture was then filtered and the filtrate concentrated underreduced pressure to give 22.45 gm (79%) ofN-(4-fluorobenzoyl)-4-aminoaniline.

Diazotization and Reduction

To a stirred suspension of 5.0 gm (23.9 mMol)N-(4-fluorobenzoyl)-4-aminoaniline in 42 mL concentrated hydrochloricacid at 0° C. was added dropwise a solution of 1.65 gm (23.9 mMol)sodium nitrite in 30 mL water. The mixture was stirred for 10 minutesafter the addition was complete and was then added dropwise to asolution of 19.6 gm (86.87 mMol) stannous chloride dihydrate in 40 mLconcentrated hydrochloric acid at 0° C. The resultant white paste wasstirred vigorously for 1 hour and was then filtered under vacuum. Thesolid which formed was then partitioned between ethyl acetate and 5Nsodium hydroxide, the phases separated and the aqueous phase wasextracted again with dichloromethane. The combined organic phases werecombined, dried over sodium sulfate and concentrated under reducedpressure to give 3.8 gm (72%) of the title compound as a brown solidwhich is suitable for use in subsequent reactions without furtherpurification.

Preparation IV2-methyl-5-amino-3-(2-(N',N'-dimethylamino]ethyl)-1H-indole

A mixture of 1.58 gm (4.65 mMol)N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamideand 40 mL 6N hydrochloric acid was heated to reflux for 4 hours. Thereaction mixture was then cooled to room temperature and then extractedwith benzene (3×70 mL). The remaining aqueous phase was treated with 5Nsodium hydroxide until pH of about 11-12. The aqueous phase was thenextracted with dichioromethane (4×100 mL) and the combined extracts weredried over sodium sulfate and concentrated under reduced pressure. Theresultant residue was subjected to silica gel chromatography, elutingwith dichloromethane containing 14% methanol and 1% ammonium hydroxide.Fractions shown to contain product were combined and concentrated underreduced pressure to give 0.71 gm (70%) of the title compound.

MS(FAB): m/e=218 (M+1)

Preparation VN-[2-methyl-3-(2-[N'-methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

A mixture of 3.74 gm (8.7 mMol)N-[2-methyl-3-(2-[N'-methyl-N'-((S)-1-phenylethyl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide,5.49 gm (87.1 mMol) ammonium formate and 0.4 gm 5% palladium on carbonin 80 mL methanol was heated at reflux for 45 minutes. The reactionmixture was filtered and the filtrate concentrated under reducedpressure. The resulting residue was subjected to flash chromatography,eluting with dichloromethane containing 20% methanol and 2% ammoniumhydroxide. Fractions shown to contain product were combined andconcentrated under reduced pressure to give 1.93 gm (68%) of the titlecompound.

m.p.=82-84° C.; MS: Exact Mass: Calculated for: C₁₉ H₂₁ N₃ OF=326.1669.Found: 326.1694.

Preparations VI and VII are typical of procedures for the synthesis ofthe 2-(pyrazol-4-yl)-1-ethanols required for the preparation ofcompounds of this invention.

Preparation VI 2-(1-methyl-1H-pyrazol-4-yl)-1-ethanol

To a mixture of 200 gm (2.85 mole) 2,3-dihydrofuran and 800 mL (4.81mole) triethylorthoformate were added 0.8 mL (6.5 mMol) borontrifluoride diethyl etherate dropwise. After an initial exotherm thereaction mixture was allowed to stir at ambient temperature for fourdays. To the reaction mixture was then added 4.0 gm potassium carbonateand the reaction mixture was distilled under 6.0 mm Hg. Fractionsdistilling between 60° C. and 130° C. were collected to give 261.64 gm(42.1%) of a light yellow oil.

MS(m/e): 219(M⁺)

To a solution of 87.2 gm (0.40 mole) of the previously prepared yellowoil in 787 mL 1N HCl were added 21.3 mL (0.40 mole) methyl hydrazine andthe reaction mixture was stirred at reflux for four hours. The reactionmixture was cooled to ambient temperature and the volatiles were removedunder reduced pressure. The residual oil was treated with 2N NaOH untilbasic and the aqueous extracted well with dichloromethane. The combinedorganic extracts were dried over sodium sulfate and concentrated underreduced pressure to give 32.15 gm (64.5%) of the title compound as abrown oil.

MS(m/e): 126(M⁺); ¹ H-NMR(DMSO-d₆): δ7.45 (s, 1H); 7.25 (s, 1H); 4.65(t, 1H); 3.75 (s,3H); 3.55 (m, 2H); 2.55 (t, 2H).

Preparation VII 2-(1-isopropyl-1H-pyrazol-4-yl)-1-ethanol

To a solution of 1.0 gm (9.0 mMol) 2-(4-pyrazolyl)-1-ethanol in 36 mLdimethylformamide were added 2.38 gm (22.5 mMol) sodium carbonatefollowed by the dropwise addition of a solution of 0.89 mL (9.0 mMol)2-iodopropane in 8 mL dimethylformamide. The reaction mixture was heatedto 100° C. for 18 hours. The reaction mixture was then cooled to ambientand then concentrated under reduced pressure. The residue waspartitioned between water and dichloromethane. The organic phase wasthen washed with water followed by saturated aqueous sodium chloride andwas then dried over sodium sulfate. The remaining organics wereconcentrated under reduced pressure to give 0.36 gm (26.0%) of the titlecompound as a brown oil.

¹ H-NMR(DMSO-d₆): δ7.50 (S, 1H); 7.25 (s, 1H); 4.60 (t, 1H); 4.40 (m,1H); 3.50 (m, 2H); 2.55 (t, 2H); 1.35(d, 6H).

Preparation VIII 1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (PEPC)

N-ethyl-N'-3-(1-pyrrolidinyl)propylurea

To a solution of 27.7 gm (0.39 mole) ethyl isocyanate in 250 mLchloroform were added 50 gm (0.39 mole) 3-(1-pyrrolidinyl)propylaminedropwise with cooling. Once the addition was complete, the cooling bathwas removed and the reaction mixture stirred at room temperature for 4hours. The reaction mixture was then concentrated under reduced pressureto give 74.5 gm (96.4%) of the desired urea as a clear oil.

1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (PEPC)

To a solution of 31.0 gm (0.156 mole)N-ethyl-N'-3-(1-pyrrolidinyl)propylurea in 500 mL dichloromethane wereadded 62.6 gm (0.62 mole) triethylamine and the solution was cooled to0° C. To this solution were then added 59.17 gm (0.31 mole)4-toluenesulfonyl chloride in 400 mL dichloromethane dropwise at such arate as to maintain the reaction at 0-5° C. After the addition wascomplete, the reaction mixture was warmed to room temperature and thenheated to reflux for 4 hours. After cooling to room temperature, thereaction mixture was washed with saturated aqueous potassium carbonate(3×150 mL). The aqueous phases were combined and extracted withdichloromethane. All organic phases were combined and concentrated underreduced pressure. The resultant orange slurry was suspended in 250 mLdiethyl ether and the solution decanted off from the solid. Theslurry/decantation process was repeated 3 more times. The ethersolutions were combined and concentrated under reduced pressure to give18.9 gm (67%) of the desired product as a crude orange oil. A portion ofthe oil was distilled under vacuum to give a colorless oil distilling at78-82° C. (0.4 mm Hg).

Preparation IX Preparation of a polymer supported form of1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (PEPC)

A suspension of 8.75 gm (48.3 mMol)1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide and 24.17 gm (24.17mMol) Merrifield's resin (2% cross-linked, 200-400 mesh,chloromethylated styrene/divinylbenzene copolymer, 1 meq. Cl/gm) indimethylformamide was heated at 100° C. for 2 days. The reaction wascooled and filtered and the resulting resin washed sequentially with 1Ldimethylformamide, 1L tetrahydrofuran and 1L diethyl ether. Theremaining resin was then dried under vacuum for 18 hours.

Preparation XN-[2-methyl-3-(2-aminoethyl)-1H-indol-5-yl]-4-fluorobenzamide

5-phthalimidyl-2-pentanone Ethylene Glycol Ketal

A mixture of 25 gm (0.15 Mol) 5-chloro-2-pentanone ethylene glycolketal, 42.2 gm (0.23 Mol) potassium phthalimidate, 150 mL ethanol and150 mL dimethylformamide was heated at reflux for 3 days. The reactionmixture was cooled to room temperature, diluted with water and extractedwith ethyl acetate. The organic extract was washed with water, driedover sodium sulfate and concentrated under reduced pressure to provide36.8 gm (88%) of the desired ketal.

5-phthalimidyl-2-pentanone

A solution of 26.8 gm (97.2 mMol) 5-phthalimidyl-2-pentanone ethyleneglycol ketal in 200 mL acetone and 200 mL 3N hydrochloric acid wasstirred at room temperature for 14 hours. The reaction mixture was thenadjusted to pH=12 with 50% sodium hydroxide and the acetone removedunder reduced pressure. The remaining aqueous phase was extracted withethyl acetate. This organic phase was washed with water, dried oversodium sulfate, and concentrated under reduced pressure to provide 15.8gm (70%) of the desired ketone.

N-2-methyl-3-2-phthalimidylethyl)-1H-indol-5-yl]-4-fluorobenzamide

To a solution of 5.33 gm (21.7 mMol)4-(4-fluorobenzoyl)aminophenylhydrazine and 5.03 gm (21.8 mMol)5-phthalimidyl-2-pentanone in 100 mL ethanol were added 2 mLconcentrated hydrochloric acid and the reaction mixture was heated at80° C. for 14 hours. To the reaction mixture were then added anadditional 3 mL concentrated hydrochloric acid and heating continued foran additional 6 hours. The reaction mixture was then cooled to 0° C. and100 mL hexane were slowly added. The solid which formed was filtered andwashed with hexane and provided, after drying, 6.67 gm of the desiredcompound. The mother liquor was concentrated under reduced pressure andthen subjected to silica gel chromatography, eluting with 1:1hexane:ethyl acetate. Fractions containing product were combined andconcentrated under reduced pressure to provide an additional 0.63 gm ofproduct. Overall yield was 7.3 gm (76%).

Removal of Phthalimidyl Moiety

A mixture of 5.63 gm (12.8 mMol)N-[2-methyl-3-(2-phthalimidylethyl)-1H-indol-5-yl]-4-fluorobenzamide,13.5 mL hydrazine hydrate, 45 mL water, and 18 mL ethanol was stirred atroom temperature for 16 hours. The reaction mixture was concentratedunder reduced pressure and the residue partitioned betweendichloromethane and saturated aqueous sodium carbonate. The phases wereseparated and the aqueous phase was extracted twice with dichloromethanecontaining 5% methanol. All organic phases wee combined, dried oversodium sulfate and concentrated under reduced pressure. The residue wassubjected to silica gel chromatography, eluting with 15% methanol indichloromethane containing 1% ammonium hydroxide. Fractions containingproduct were combined and concentrated under reduced pressure to provide3.5 gm (89%) of the title amine as a solid.

m.p.=80-82° C.; MS(m/e): 311(M⁺)

The Fischer indolization conditions described in detail in Example 1 aretypical of those required to prepare the compounds of the presentinvention.

EXAMPLE 1N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamidehydrochloride

To a solution of 4.00 gm (30.96 mMol) N,N-dimethyl-5-amino-2-pentanoneand 7.74 gm (31.6 mMol) N-(4-fluorobenzoyl)-4-aminohydrazine in 140 mLethanol were added 1.5 mL concentrated hydrochloric acid and thereaction mixture was heated to reflux for 3 hours. At this point anadditional 6.0 mL concentrated hydrochloric acid were added and thereflux was continued for 36 hours. The reaction mixture was concentratedto half volume under reduced pressure and was then diluted with 300 mLdichloromethane followed by 200 mL 1N sodium hydroxide. The organicphase was separated and the aqueous phase extracted dichloromethane(4×150 mL). The organic extracts were combined, dried over sodiumsulfate and concentrated under reduced pressure. The resulting residuewas subjected to flash chromatography, eluting with dichloromethanecontaining 10% methanol and 1% ammonium hydroxide. Fractions shown tocontain product were combined and concentrated under reduced pressure togive 6.66 gm (63.3%)N-[2-methyl-3-(2-[N',N'-dimethylaminolethyl)-1H-indol-5-yl]-4-fluorobenzamide.This material was converted to the hydrochloride salt, crystallizingfrom ethanol/diethyl ether to give the title compound.

m.p.=281-283° C.; MS: m/e=339 (M⁺); Calculated for C₂₀ H₂₂ N₃ OF.HCl:Theory: C, 63.91; H, 6.17; N, 11.18. Found: C, 64.20; H, 6.29; N, 11.20.

EXAMPLE 2N-[2-methyl-3-(2-[N'-methyl-N'-((S)-1-phenylethyl)amino]-ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Following the procedure described in detail in Example 1, 5.32 gm (21.7mMol) N-(4-fluorobenzoyl)-4-aminohydrazine and 2.95 gm (13.45 mMol)N-methyl-N-((S)-1-phenylethyl)-5-amino-2-pentanone were reacted togetherto prepare 4.988 gm (86%) of the title compound.

m.p.=65-67° C.; MS: m/e=430 (M+1); Calculated for C₂₇ H₂₈ N₃ OF: Theory:C, 75.50; H, 6.57; N, 9.78. Found: C, 75.28; H, 6.75; N, 9.93.

EXAMPLE 3N-[2-methyl-3-(2-[N'-methyl-N'-ethylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

A mixture of 0.125 gm (0.38 mMol)N-[2-methyl-3-(2-(N'-methylamino)ethyl)-1H-indol-5-yl)-4-fluorobenzamide,0.033 mL (0.41 mMol) ethyl iodide and 0.105 gm (0.76 mMol) potassiumcarbonate in 4.0 mL acetonitrile was heated at reflux for 6 hours. Tothe reaction mixture were then added 15.0 mL water and 40 mLdichloromethane. The phases were separated and the aqueous phase wasextracted with dichloromethane (2×15 mL). The combined organic phaseswere dried over sodium sulfate and concentrated under reduced pressure.The resultant residue was subjected to silica gel chromatography,eluting with dichloromethane containing 10% methanol and 1% ammoniumhydroxide. Fractions shown to contain product were combined andconcentrated under reduced pressure to give 0.040 gm (30%) of the titlecompound.

m.p.=79-81° C.; MS: m/e=353 (M⁺)

The compounds of Examples 4-8 were prepared by the procedure describedin detail in Example 3.

EXAMPLE 4N-(2-methyl-3-(2-(N'-methyl-N'-propylamino)ethyl)-1H-indol-5-yl)-4-fluorobenzamidehydrobromide

Beginning with 0.152 gm (0.467 mMol)N-[(2-methyl-3-(2-[N'-methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamideand 0.068 mL (0.697 mMol) 1-iodopropane, 0.071 gm (41%) ofN-[2-methyl-3-(2-[N'-methyl-N-propylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamidewere prepared. The hydrobromide salt was prepared and crystallized fromethanol/diethyl ether to give the title compound.

m.p.=97-99° C.; MS: Exact Mass: Calculated for: C₂₂ H₂₇ N₃ OF=368.2138.Found: 368.2135.

EXAMPLE 5N-[2-methyl-3-(2-[N'-methyl-N'-cyclohexylmethylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamidehydrobromide

Beginning with 0.166 gm (0.51 mMol)N-[2-methyl-3-(2-[N'-methylamino]ethyl-1H-indol-5-yl]-4-fluorobenzamideand 0.085 mL (0.61 mMol) cyclohexylmethyl bromide, 0.170 gm (79%) ofN-[2-methyl-3-(2-[N'-methyl-N'-cyclopropylmethylamino]-ethyl)-1H-indol-5-yl]-4-fluorobenzamidewere prepared. The hydrobromide salt was prepared and crystallized fromethanol/diethyl ether to give the title compound.

m.p.=195-198° C.; MS: m/e=422 (M+1); Calculated for C₂₆ H₃₃ N₃ OF.HBr:Theory: C, 62.05; H, 6.62; N. 8.36. Found: C, 61.96; H, 6.71; N, 8.25.

EXAMPLE 6N-[2-methyl-3-(2-[N'-methyl-N'-(2-phenylethyl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamidehydrochloride

Beginning with 0.215 gm (0.66 mMol)N-[(2-methyl-3-(2-[N'-methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamideand 0.12 mL (0.88 mMol) 2-phenylethyl bromide, 0.225 gm (80%) ofN-[2-methyl-3-(2-[N'-methyl-N'-(2-phenylethyl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamidewere prepared. The hydrochloride salt was prepared and crystallized fromethanol/diethyl ether to give the title compound.

m.p.=221-223° C.; MS: m/e=429 (M⁺); Calculated for C₂₇ H₂₈ N₃ OF.HCl:Theory: C, 69.59; H, 6.27; N, 9.02. Found: C, 69.84; H, 6.38; N, 8.87.

EXAMPLE 7N-[2-methyl-3-(2-[N'-methyl-N'-(4-pyridinylmethyl)-amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.139 gm (0.43 mMol)N-[2-methyl-3-(2-[N'-methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamideand 0.100 gm (0.61 mMol) 4-pyridinylmethyl chloride hydrochloride, 0.145gm (82%) of the title compound were prepared.

m.p.=77-80° C.; MS: m/e=416 (M⁺); MS: Exact Mass: Calculated for C₂₅ H₂₆N₄ OF=417.2091. Found: 417.2082.

EXAMPLE 8N-[2-methyl-3-(2-[N'-methyl-N'-(2-[1-methylpyrazol-4-yl]-ethyl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamidehydrochloride

Beginning with 0.209 gm (0.64 mMol)N-[(2-methyl-3-(2-[N'-methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamideand 0.195 gm (0.95 mMol)2-(1-methyl-1H-pyrazol-3-yl)-1-methanesulfonyloxyethane, 0.204 gm (74%)ofN-[2-methyl-3-(2-[N'-methyl-N'-(2-[1-methylpyrazol-4-yl]ethyl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamidewere recovered. This compound was converted to its hydrochloride salt,crystallizing from ethanol/diethyl ether to give the title compound.

m.p.=84-86° C.; MS: m/e=433 (M⁺); MS: Exact Mass: Calculated for C₂₅ H₂₉N₅ OF=434.2356. Found: 434.2363.

EXAMPLE 9N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-4-methylthiobenzamide

A mixture of 0.142 gm (0.65 mMol)2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole, 0.12 gm(0.71 mMol) 4-methylthiobenzoic acid, 0.096 gm (0.71 mMol)1-hydroxybenzotriazole, and 0.136 gm (0.71 mMol)1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) in 8mL dimethylformamide and 1 mL tetrahydrofuran was stirred at roomtemperature under a nitrogen atmosphere for 48 hours. The the mixturewere then added 50 mL dichloromethane, 5 mL 2N sodium hydroxide and 50mL water. The phases were separated and the aqueous layer extracted withdichloromethane (3×30 mL). The combined organic layers were dried oversodium sulfate and concentrated under reduced pressure. The resultingresidue was subjected to silica gel chromatography, eluting withdichloromethane containing 10% methanol and 1% ammonium hydroxide.Fractions shown to contain product were combined and concentrated underreduced pressure to give 0.134 gm (56%) of the title compound.

m.p.=87-91° C.; MS: Exact Mass: Calculated for C₂₁ H₂₆ N₃ OS=368.1797.Found: 368.1808.

The compounds of Examples 10-14 were prepared by the procedure describedin detail in Example 9.

EXAMPLE 10N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-4-(N",N"-dimethylamino)benzamide

Beginning with 0.148 gm (0.68 mMol)2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.113 gm(0.68 mMol) 4-(dimethylamino)benzoic acid, 0.080 gm (32%) of the titlecompound were recovered.

m.p.=100-104° C. (decomp.); Calculated for C₂₂ H₂₈ N₄ O: Theory: C,72.50; H, 7.74; N, 15.37. Found: C, 72.26; H, 7.56; N, 15.33.

EXAMPLE 11N-(2-methyl-3-(2-(N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-4-acetamidobenzamide

Beginning with 0.130 gm (0.598 mMol)2-methyl-5-amino-3-(2-(N',N'-dimethylamnino)ethyl)-1H-indole and 0.107gm (0.598 mMol) 4-acetamidobenzoic acid, 0.130 gm (32%) of the titlecompound were recovered.

m.p.=134-138° C.; MS: Exact Mass: Calculated for C₂₂ H₂₆ N4O₂ =379.2134.Found: 379.2142.

EXAMPLE 12N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-4-(2-methyl-4-fluoro)benzamide

Beginning with 0.148 gm (0.68 mMol)2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.115 gm(0.75 mMol) 2-methyl-4-fluorobenzoic acid, 0.206 gm (86%) of the titlecompound were recovered.

m.p.=71-75° C.; MS: Exact Mass: Calculated for C₂₁ H₂₅ N₃ OF=354.1982.Found: 354.1993.

EXAMPLE 13N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2-acetamido-4-fluorobenzamide

Beginning with 0.150 gm (0.69 mMol)2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.150 gm(0.76 mMol) 2-acetamido-4-fluorobenzoic acid, 0.150 gm (55%) of thetitle compound were recovered.

m.p.=183-187° C.; MS(FD): m/e=396 (M⁺)

EXAMPLE 14N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-6-fluoropyridin-3-ylcarboxamide

Beginning with 0.141 gm (0.65 mMol)2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.101 gm(0.71 mMol) 6-fluoro-3-pyridinecarboxylic acid, 0.0935 gm (42%) of thetitle compound were recovered.

m.p.=165-168° C.; MS: Exact Mass: Calculated for C19H₂₂ N₄ OF=341.1778.Found: 341.1783.

EXAMPLE 15N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2-chloro-4-fluorobenzamidehydrobromide

To a stirred solution of 0.115 gm (0.66 mMol) 2-chloro-4-fluorobenzoicacid in 2 mL dimethylformaide were added 0.107 gm (0.66 mMol)carbonyldiimidazole (CDI) and immediate gas evolution was observed. Thereaction mixture was stirred for 5 hours at room temperature and then0.131 gm (0.60 mMol)2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole were added.The resulting mixture was stirred at room temperature for 72 hours. Thereaction mixture was then concentrated under reduced pressure and theresidue subjected to silica gel chromatography. The material isolatedwas further purified by silica gel chromatography, eluting withdichloromethane containing 7% methanol and 1% ammonium hydroxide.Fractions shown to contain product were combined and concentrated underreduced pressure to give 0.107 gm (43%) ofN-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2-chloro-4-fluorobenzamide.The hydrobromide salt was formed and crystallized from ethanol/diethylether to give the title compound.

m.p. 66-68° C.; MS: m/e=373 (M⁺)

EXAMPLE 16N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,4-difluorobenzamidehydrochloride

To a stirred solution of 0.135 gm (0.62 mMol)2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole in 6 mLdichloromethane and 0.2 mL pyridine at 0° C. were added 0.09 mL (0.73mMol) 2,4-difluorobenzoyl chloride. The reaction mixture was warmed toroom temperature and stirred for 2 hours at room temperature. Thereaction mixture was then diluted with 20 mL dichloromethane and washedwith 4 mL 2N sodium hydroxide. The organic phase was separated and theaqueous phase extracted again with dichloromethane. The organic phaseswere combined, dried over sodium sulfate and concentrated under reducedpressure. The residue was subjected to silica gel chromatography,eluting with dichloromethane containing 8% methanol and 1% ammoniumhydroxide. Fractions shown to contain product were combined andconcentrated under reduced pressure to give 0.110 gm (50%) ofN-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,4-difluorobenzamide.The hydrochloride salt was formed and crystallizing from ethanol/diethylether to give the title compound.

m.p.=269-271° C.; MS: m/e=357 (M⁺); Calculated for C₂₀ H₂₁ N₃ OF₂ :Theory: C, 60.99; H, 5.63; N, 10.67. Found: C, 61.24; H, 5.74; N, 10.67.

General Procedure for the Coupling of Carboxylic Acids with5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole

To a suspension of 0.120 gm (0.11 mMol) of polymer bound1-ethyl-3-(3-(1-pyrrolidinylpropyl)carbodiimide (Preparation IX) in 2 mLchloroform are added 6 mg (0.027 mMol) of5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055 mMol of thedesired carboxylic acid. The reaction is agitated for 48 hours at roomtemperature. The resin is removed by filtration and the product isolatedby evaporation of solvent. This procedure is illustrated by Examples17-34.

EXAMPLE 17N-[2-methyl-3-(2-([N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-isobutyramide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055mMol of isobutyric acid, the title compound was prepared in 60% yield.

MS: m/e=390 (M⁺)

EXAMPLE 18N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-cyclopropanecarboxylicamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055mMol of cyclopropanecarboxylic acid, the title compound was prepared in65% yield.

EXAMPLE 19N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-3-trifluoromethylbenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055mMol of 3-trifluoroinethylbenzoic acid, the title compound was preparedin 55% yield.

MS: m/e=390 (M⁺)

EXAMPLE 20N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-3,5-dichlorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055mMol of 3,5-dichlorobenzoic acid, the title compound was prepared in 55%yield.

EXAMPLE 21N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2-methoxy-4-chlorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055mMol of 2-methoxy-4-chlorobenzoic acid, the title compound was preparedin 33% yield.

MS: m/e=386 (M⁺)

EXAMPLE 22N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2-chloro-4-nitrobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055mMol of 2-chloro-4-nitrobenzoic acid, the title compound was prepared in27% yield.

MS: m/e=401 (M⁺)

EXAMPLE 23N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2-furylcarboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055mMol of 2-furylcarboxylic acid, the title compound was prepared in 67%yield.

EXAMPLE 24N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-3-furylcarboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055mMol of 3-furylcarboxylic acid, the title compound was prepared in 65%yield.

EXAMPLE 25N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-5-methyl-2-furylcarboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055mMol of 5-methyl-2-furylcarboxylic acid, the title compound was preparedin 66% yield.

MS: m/e=326 (M⁺)

EXAMPLE 26N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2-methyl-3-furylcarboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055mMol of 2-methyl-3-furylcarboxylic acid, the title compound was preparedin 32% yield.

MS: m/e=326 (M⁺)

EXAMPLE 27N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-5-methyl-3-furylcarboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055mMol of 5-methyl-3-furylcarboxylic acid, the title compound was preparedin 32% yield.

MS: m/e=326 (M⁺)

EXAMPLE 28N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-5-chloro-2-furylcarboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055mMol of 5-chloro-2-furylcarboxylic acid, the title compound was preparedin 42% yield.

MS: m/e=346 (M⁺)

EXAMPLE 29N-[2-methyl-3-(2-(N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-3-thienylcarboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055mMol of 3-thienylcarboxylic acid, the title compound was prepared in 32%yield.

MS: m/e=328 (M⁺)

EXAMPLE 30N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-3-methyl-2-thienylcarboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055mMol of 3-methyl-2-thienylcarboxylic acid, the title compound wasprepared in 50% yield.

MS: m/e=342 (M⁺)

EXAMPLE 31N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-5-methyl-2-thienylcarboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055mMol of 5-methyl-2-thienylcarboxylic acid, the title compound wasprepared in 33% yield.

EXAMPLE 32N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-5-bromo-2-thienylcarboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055mMol of 5-bromo-2-thienylcarboxylic acid, the title compound wasprepared in 35% yield.

EXAMPLE 33N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-5-chloro-2-thienylcarboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055mMol of 5-chloro-2-thienylcarboxylic acid, the title compound wasprepared in 25% yield.

MS: m/e=362 (M⁺)

EXAMPLE 34N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-3-pyridinecarboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.055mMol of 3-pyridine-carboxylic acid, the title compound was prepared in33% yield.

MS: m/e=323 (M⁺)

General Procedure for the Coupling of Carboxylic Acid Halides with5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole

To a suspension of 0.041 gm (0.056 mMol) of polymer bound4-(N,N-dimethylamino)pyridine in 2 mL chloroform are added 6 mg (0.027mMol) of 2-methyl-5-amino-3-(2-(N',N'-dimethyl-amino)ethyl)-1H-indoleand 0.035 mMol of the desired carboxylic acid halide. The reaction isagitated for 24 hours at room temperature. To the reaction mixture arethen added 0.07 gm (0.056 mMol) aminomethylated polystyrene and thereaction agitated for an additional 24 hours. The resin is removed byfiltration and the product isolated by evaporation of solvent. Thisprocedure is illustrated by Examples 35-83.

EXAMPLE 35N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-acetamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of acetyl chloride, the title compound was prepared in 50% yield.

MS: m/e=260 (M⁺)

EXAMPLE 36N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-propanamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethy-lamino)ethyl)-1H-indole and 0.035mMol of propanoyl chloride, the title compound was prepared in 73%yield.

MS: m/e=274 (M⁺)

EXAMPLE 37N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-isobutyramide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of isobutyryl chloride, the title compound was prepared in 67%yield.

MS: m/e=288 (M⁺)

EXAMPLE 38N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-4-methylpentanamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 4-methyl-pentanoyl chloride, the title compound was prepared in70% yield.

MS: m/e=316 (M⁺)

EXAMPLE 39N-(2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-cyclobutanecarboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of cyclobutane-carbonyl chloride, the title compound was preparedin 69% yield.

MS: m/e=300 (M⁺)

EXAMPLE 40N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-cyclopentanecarboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of cyclo-pentanecarbonyl chloride, the title compound was preparedin 63% yield.

MS: m/e=314 (M⁺)

EXAMPLE 41N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-cyclohexanecarboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of cyclohexane-carbonyl chloride, the title compound was preparedin 80% yield.

MS: m/e=328 (M⁺)

EXAMPLE 42N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-benzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of benzoyl chloride, the title compound was prepared in 83% yield.

MS: m/e=321 (M⁺)

EXAMPLE 43N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 4-fluorobenzoyl chloride, the title compound was prepared in 73%yield.

MS: m/e=339 (M⁺)

EXAMPLE 44N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-3-fluorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimetylamino)ethyl)-1H-indole and 0.035mMol of 3-fluorobenzoyl chloride, the title compound was prepared in 63%yield.

MS: m/e=340 (M+1)

EXAMPLE 45N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2-fluorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 2-fluorobenzoyl chloride, the title compound was prepared in 76%yield.

MS: m/e=340 (M+1)

EXAMPLE 46N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-3-chlorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 3-chlorobenzoyl chloride, the title compound was prepared in 62%yield.

MS: m/e=356 (M⁺)

EXAMPLE 47N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-4-chlorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 4-chlorobenzoyl chloride, the title compound was prepared in 66%yield.

EXAMPLE 48N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-4-methylbenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 4-methylbenzoyl chloride, the title compound was prepared in 84%yield.

MS: m/e=336 (M⁺)

EXAMPLE 49N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2-methylbenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 2-methylbenzoyl chloride, the title compound was prepared in 95%yield.

MS: m/e=336 (M⁺)

EXAMPLE 50N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-4-trifluoromethylbenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 4-trifluoromethylbenzoyl chloride, the title compound wasprepared in 87% yield.

MS: m/e=390 (M⁺)

EXAMPLE 51N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2-trifluoromethylbenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 2-trifluoromethylbenzoyl chloride, the title compound wasprepared in 89% yield.

MS: m/e=390 (M⁺)

EXAMPLE 52N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-4-methoxycarbonylbenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 4-methoxycarbonylbenzoyl chloride, the title compound wasprepared in 78% yield.

MS: m/e=380 (M⁺)

EXAMPLE 53N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-4-methoxybenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 4-methoxbenzoyl chloride, the title compound was prepared in 64%yield.

MS: m/e=351 (M⁺)

EXAMPLE 54N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-4-phenylbenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 4-phenylbenzoyl chloride, the title compound was prepared in 91%yield.

MS: m/e=398 (M⁺)

EXAMPLE 55N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,3-difluorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 2,3-difluorobenzoyl chloride, the title compound was prepared in76% yield.

MS: m/e=358 (M⁺)

EXAMPLE 56N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,6-difluorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 2,6-difluorobenzoyl chloride, the title compound was prepared in65% yield.

EXAMPLE 57N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-3,5-difluorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 3,5-difluorobenzoyl chloride, the title compound was prepared in85% yield.

EXAMPLE 58N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-3,4-difluorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 3,4-difluorobenzoyl chloride, the title compound was prepared in75% yield.

EXAMPLE 59N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,5-difluorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 2,5-difluorobenzoyl chloride, the title compound was prepared in86% yield.

MS: m/e=358 (M⁺)

EXAMPLE 60N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-3,4-dichlorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 3,4-dichlorobenzoyl chloride, the title compound was prepared in69% yield.

EXAMPLE 61N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,6-dichlorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 2,6-dichlorobenzoyl chloride, the title compound was prepared in69% yield.

EXAMPLE 62N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,4-dichlorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 2,4-dichlorobenzoyl chloride, the title compound was prepared in64% yield.

MS: m/e=392 (M+1)

EXAMPLE 63N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,3-dichlorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 2,3-dichlorobenzoyl chloride, the title compound was prepared in61% yield.

MS: m/e=392 (M-1)

EXAMPLE 64N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,3,6-trifluorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 2,3,6-trifluorobenzoyl chloride, the title compound was preparedin 86% yield.

MS: m/e=376 (M⁺)

EXAMPLE 65N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,3,4-trifluorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 2,3,4-trifluorobenzoyl chloride, the title compound was preparedin 70% yield.

EXAMPLE 66N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,4,5-trifluorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 2,4,5-trifluorobenzoyl chloride, the title compound was preparedin 81% yield.

EXAMPLE 67N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,4,6-trifluorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 2,4,6-trifluorobenzoyl chloride, the title compound was preparedin 76% yield.

EXAMPLE 68N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,4,6-trichlorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 2,4,6-trichlorobenzoyl chloride, the title compound was preparedin 59% yield.

EXAMPLE 69N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2-trifluoromethyl-4-fluorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 2-trifluoromethyl-4-fluorobenzoyl chloride, the title compoundwas prepared in 49% yield.

EXAMPLE 70N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-4-trifluoromethyl-2-fluorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 4-trifluoromethyl-2-fluorobenzoyl chloride, the title compoundwas prepared in 71% yield.

EXAMPLE 71N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2-trifluoromethyl-6-fluorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 2-trifluoromethyl-6-fluorobenzoyl chloride, the title compoundwas prepared in 66% yield.

EXAMPLE 72N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-3-trifluoromethyl-4-fluorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 3-trifluoromethyl-4-fluorobenzoyl chloride, the title compoundwas prepared in 75% yield.

EXAMPLE 73N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,4-dichloro-5-fluorobenzamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 2,4-dichloro-5-fluorobenzoyl chloride, the title compound wasprepared in 75% yield.

EXAMPLE 74N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-thiophene-2-carboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of thiophene-2-carbonyl chloride, the title compound was preparedin 63% yield.

MS: m/e=328 (M⁺)

EXAMPLE 75N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-isoxazole-5-carboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of isoxazole-5-carbonyl chloride, the title compound was preparedin 63% yield.

EXAMPLE 76N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2-chloropyridine-3-carboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 2-chloropyridine-3-carbonyl chloride, the title compound wasprepared in 60% yield.

EXAMPLE 77N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-6-chloropyridine-3-carboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 6-chloropyridine-3-carbonyl chloride, the title compound wasprepared in 68% yield.

EXAMPLE 78N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-3-chlorothiophene-2-carboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of 3-chlorothiophene-2-carbonyl chloride, the title compound wasprepared in 77% yield.

MS: m/e=362 (M⁺)

EXAMPLE 79N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-naphthalene-2-carboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of naphthalene-2-carbonyl chloride, the title compound was preparedin 67% yield.

MS: m/e=372 (M⁺)

EXAMPLE 80N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-naphthalene-1-carboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of naphthalene-1-carbonyl chloride, the title compound was preparedin 77% yield.

MS: m/e=372 (M⁺)

EXAMPLE 81N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-benzothiophene-2-carboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of benzothiophene-2-carbonyl chloride, the title compound wasprepared in 53% yield.

MS: m/e=378 (M⁺)

EXAMPLE 82N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-quinoxaline-2-carboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of quinoxaline-2-carbonyl chloride, the title compound was preparedin 67% yield.

MS: m/e=374 (M⁺)

EXAMPLE 83N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-quinoline-2-carboxamide

Beginning with 0.027 mMol of2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035mMol of quinoline-2-carbonyl chloride, the title compound was preparedin 86% yield.

MS: m/e=372 (M⁺)

General Procedures for the Reductive Alkylation of Secondary Amines ofFormula III Procedure A

A solution of 1 equivalent amine (III), 2-3 equivalents of aldehyde, and2 molar equivalents of sodium cyanoborohydride in 4:1 methanol:aceticacid is mixed well and allowed to stand for 24 hours at room temperaturefor from 3 to 24 hours. The reaction mixture is then loaded onto aVARIAN BOND ELUT SCX™ (Varian, Harbor City, Calif., U.S.A.) ion exchangecolumn. The column is eluted with several volumes of methanol and isthen eluted with either saturated methanolic hydrogen chloride or 2Mammonia in methanol. Fractions from the column containing product areconcentrated under reduced pressure. Compounds eluted with methanolichydrogen chloride provide the hydrochloride salts, and compounds elutedwith ammonia in methanol provide the free bases, of compounds of theinvention.

Procedure B

A solution of 1 equivalent of secondary amine (III), 1.2 equivalents ofaldehyde, 12 equivalents of sodium triacetoxyborohydride, and 0.3equivalents of acetic acid in dichloromethane is mixed for 24 hours atroom temperature. The compounds of the invention are isolated asdescribed in PROCEDURE A.

The compounds of Examples 84-89 were prepared by PROCEDURE A.

EXAMPLE 84N-[2-methyl-3-(2-[N'-methyl-N'-(2-thienyl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.025 mMol ofN-[2-methyl-3-(2-[N'-methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation V) and 0.075 mMol of thiophene-2-carboxaldehyde, the titlecompound was prepared in 91% yield.

EXAMPLE 85N-[2-methyl-3-(2-[N'-methyl-N'-(3-thienyl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.025 mMol ofN-[2-methyl-3-(2-[N'-methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation V) and 0.075 mMol of thiophene-3-carboxaldehyde, the titlecompound was prepared in 80% yield.

EXAMPLE 86N-[2-methyl-3-(2-[N'-methyl-N'-(2-furyl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.025 mMol ofN-[2-methyl-3-(2-[N'-methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation V) and 0.075 mMol of 2-furaldehyde, the title compound wasprepared in 83% yield.

EXAMPLE 87N-[2-methyl-3-(2-[N'-methyl-N'-(2-pyridyl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.025 mMol ofN-[2-methyl-3-(2-[N'-methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation V) and 0.075 mMol of pyridine-2-carboxaldehyde, the titlecompound was prepared in 94% yield.

EXAMPLE 88N-[2-methyl-3-(2-[N'-methyl-N'-(3-pyridyl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.025 mMol ofN-[2-methyl-3-(2-[N'-methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation V) and 0.075 mMol of pyridine-3-carboxaldehyde, the titlecompound was prepared in 84% yield.

EXAMPLE 89N-[2-methyl-3-(2-[N'-methyl-N'-(3-indolyl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.025 mMol ofN-[2-methyl-3-(2-[N'-methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation V) and 0.075 mMol of indole-3-carboxaldehyde, the titlecompound was prepared in 100% yield.

The compounds of Examples 90-94 were prepared by PROCEDURE B.

EXAMPLE 90N-[2-methyl-3-(2-[N'-methyl-N'-(1-methylpyrrol-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.017 mMol ofN-[2-methyl-3-(2-[N'-methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation V) and 0.021 mMol of 1-methylpyrrole-2-carboxaldehyde, thetitle compound was prepared.

EXAMPLE 91N-[2-methyl-3-(2-[N'-methyl-N'-(5-methylthien-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.017 mMol ofN-[2-methyl-3-(2-[N'-methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation V) and 0.021 mMol of 5-methylthiophene-2-carboxaldehyde,the title compound was prepared.

EXAMPLE 92N-[2-methyl-3-(2-[N'-methyl-N'-(5-hydroxymethylfur-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.017 mMol ofN-[2-methyl-3-(2-[N'-methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation V) and 0.021 mMol of 5-hydroxymethylfuran-2-carboxaldehyde,the title compound was prepared.

EXAMPLE 93N-[2-methyl-3-(2-[N'-methyl-N'-(3-methylbenzothiophen-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.017 mMol ofN-[2-methyl-3-(2-[N'-methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation V) and 0.021 mMol of3-methylbenzothiophene-2-carboxaldehyde, the title compound wasprepared.

EXAMPLE 94N-[2-methyl-3-(2-[N'-methyl-N'-(5-chloro-1,3-benzodioxol-4-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.017 mMol ofN-[2-methyl-3-(2-[N'-methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation V) and 0.021 mMol of5-chloro-1,3-benzodioxole-4-carboxaldehyde, the title compound wasprepared.

General Procedures for Sequential Reductive Alkylations with AldehydesProcecure C

An equivalent of a suitable primary amine and two equivalents of asuitable aldehyde are dissolved in methanol and shaken for 1 hour. Thesolution is treated with an excess of sodium borohydride and shaken for3 hours. The reaction mixture is then passed over a VARIAN BOND ELUTSCX™ (Varian, Harbor City, Calif., U.S.A.) ion exchange column which hasbeen preactivated with 10% acetic acid in methanol. The column is washedthoroughly with methanol and then the product is eluted with 2M ammoniain methanol. The secondary amine products are then isolated byconcentration of eluant.

Procedure D

Alternatively, the reaction mixture containing the secondary amine istreated directly with an excess of a second aldehyde, acetic acid andsodium cyanoborohydride. The reaction mixture is agitated until all ofthe secondary amine is consumed, typically from 1 to 5 days, and thedesired products isolated by subjecting the reaction mixture to theisolation procedure described in PROCEDURE C.

The compounds of Examples 95-105 were prepared by PROCEDURE C.

EXAMPLE 95N-[2-methyl-3-(2-[N'-(fur-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.05 mMol ofN-[2-methyl-3-(2-aminoethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation X) and 0.1 mMol of furan-2-carboxaldehyde, the titlecompound was prepared.

MS(m/e): 392(M+1)

EXAMPLE 96N-[2-methyl-3-(2-[N'-(fur-3-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.05 mMol ofN-[2-methyl-3-(2-aminoethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation X) and 0.1 mMol of furan-3-carboxaldehyde, the titlecompound was prepared.

MS(m/e): 391(M⁺)

EXAMPLE 97N-[2-methyl-3-(2-[N'-(thiazol-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.05 mMol ofN-(2-methyl-3-(2-aminoethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation X) and 0.1 mMol of thiazole-2-carboxaldehyde, the titlecompound was prepared.

MS(m/e): 409(M+1)

EXAMPLE 98N-[2-methyl-3-(2-(N'-(imidazol-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.05 mMol ofN-[2-methyl-3-(2-aminoethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation X) and 0.1 mMol of imidazole-2-carboxaldehyde, the titlecompound was prepared.

MS(m/e): 392(M+1)

EXAMPLE 99N-[2-methyl-3-(2-[N'-(quinolin-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.05 mMol ofN-[2-methyl-3-(2-aminoethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation X) and 0.1 mMol of quinoline-2-carboxaldehyde, the titlecompound was prepared.

MS(m/e): 452(M⁺)

EXAMPLE 100N-[2-methyl-3-(2-[N'-(quinolin-4-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.05 mMol ofN-[2-methyl-3-(2-aminoethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation X) and 0.1 mMol of quinoline-4-carboxaldehyde, the titlecompound was prepared.

MS(m/e): 453(M+1)

EXAMPLE 101N-[2-methyl-3-(2-[N'-(2-phenylpropyl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.05 mMol ofN-[2-methyl-3-(2-aminoethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation X) and 0.1 mMol of 2-phenylpropanal, the title compound wasprepared.

MS(m/e): 429(M⁺)

EXAMPLE 102N-[2-methyl-3-(2-(N'-(5-hydroxymethylfur-2-yl)methylamino]-ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.05 mMol ofN-[2-methyl-3-(2-aminoethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation X) and 0.1 mMol of 5-hydroxymethylfuran-2-carboxaldehyde,the title compound was prepared.

MS(m/e): 422(M+1)

EXAMPLE 103N-[2-methyl-3-(2-N'-(5-methylimidazol-4-yl)methylamino]-ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.05 mMol ofN-[2-methyl-3-(2-aminoethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation X) and 0.1 mMol of 5-methylimidazole-2-carboxaldehyde, thetitle compound was prepared.

MS(m/e): 406(M+1)

EXAMPLE 104N-[2-methyl-3-(2-[N'-(3-methylbenzothiophen-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.05 mMol ofN-[2-methyl-3-(2-aminoethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation X) and 0.1 mMol of 3-methylbenzothiophene-2-carboxaldehyde,the title compound was prepared.

MS(m/e): 472(M+1)

EXAMPLE 105N-[2-methyl-3-(2-[N'-(3,5-dimethyl-4-ethoxycarbonylindol-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.05 mMol ofN-[2-methyl-3-(2-aminoethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation X) and 0.1 mMol of3,5-dimethyl-4-ethoxycarbonylindole-2-carboxaldehyde, the title compoundwas prepared.

MS(m/e): 491(M+1)

The compounds of Examples 106-116 were prepared by PROCEDURE D.

EXAMPLE 106N-[2-methyl-3-(2-[N'-methyl-N'-(fur-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with a methanol solution ofN-[2-methyl-3-(2-[N'-(fur-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Example 95) and 0.5 mMol of paraformaldehyde, the title compound wasprepared.

MS(m/e): 406(M+1)

EXAMPLE 107N-[2-methyl-3-(2-[N'-methyl-N'-(fur-3-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with a methanol solution ofN-[2-methyl-3-(2-[N'-(fur-3-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Example 96) and 0.5 mMol of paraformaldehyde, the title compound wasprepared.

MS(m/e): 405(M⁺)

EXAMPLE 108N-[2-methyl-3-(2-[N'-methyl-N'-(thiazol-2-yl)methylamino]-ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with a methanol solution ofN-[2-methyl-3-(2-[N'-(thiazol-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Example 97) and 0.5 mMol of paraformaldehyde, the title compound wasprepared.

MS(m/e): 423(M+1)

EXAMPLE 109N-[2-methyl-3-(2-[N'-methyl-N'-(imidazol-2-yl)methylamino]-ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with a methanol solution ofN-[2-methyl-3-(2-[N'-(imidazol-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Example 98) and 0.5 mMol of paraformaldehyde, the title compound wasprepared.

MS(m/e): 406(M+1)

EXAMPLE 110N-[2-methyl-3-(2-[N'-methyl-N'-(quinolin-2-yl)methylamino]-ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with a methanol solution ofN-[2-methyl-3-(2-[N'-(quinolin-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Example 99) and 0.5 mMol of paraformaldehyde, the title compound wasprepared.

MS(m/e): 467(M+1)

EXAMPLE 111N-[2-methyl-3-(2-[N'-methyl-N'-(quinolin-4-yl)methylamino]-ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with a methanol solution ofN-[2-methyl-3-(2-[N'-(quinolin-4-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Example 100) and 0.5 mMol of paraformaldehyde, the title compound wasprepared.

MS(m/e): 467(M+1)

EXAMPLE 112N-[2-methyl-3-(2-[N'-methyl-N'-(2-phenylpropyl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with a methanol solution ofN-[2-methyl-3-(2-[N'-(2-phenylpropyl)amino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Example 101) and 0.5 mMol of paraformaldehyde, the title compound wasprepared.

MS(m/e): 444(M⁺)

EXAMPLE 113N-[2-methyl-3-(2-[N'-methyl-N'-(5-hydroxymethylfur-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with a methanol solution ofN-[2-methyl-3-(2-[N'-(5-hydroxymethylfur-2-yl)methylaminolethyl)-1H-indol-5-yl]-4-fluorobenzamide(Example 102) and 0.5 mMol of paraformaldehyde, the title compound wasprepared.

MS(m/e): 436(M+1)

EXAMPLE 114N-[2-methyl-3-(2-[N'-methyl-N'-(5-methylimidazol-4-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with a methanol solution ofN-[2-methyl-3-(2-[N'-(5-methylimidazol-4-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Example 103) and 0.5 mMol of paraformaldehyde, the title compound wasprepared.

MS(m/e): 420(M+1)

EXAMPLE 115N-[2-methyl-3-(2-[N'-methyl-N'-(3-methylbenzothiophen-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with a methanol solution ofN-[2-methyl-3-(2-[N'-(3-methylbenzothiophen-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Example 104) and 0.5 mMol of paraformaldehyde, the title compound wasprepared.

MS(m/e): 486(M⁺)

EXAMPLE 116N-[2-methyl-3-(2-[N'-methyl-N'-(3,5-dimethyl-4-ethoxycarbonylindol-2-yl)methylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with a methanol solution ofN-[2-methyl-3-(2-[N'-(3,5-dimethyl-4-ethoxycarbonylindol-2-yl)methylamino]-ethyl)-1H-indol-5-yl]-4-fluorobenzamide(Example 105) and 0.5 mMol of paraformaldehyde, the title compound wasprepared.

MS(m/e): 506(M+1)

General Procedure for Reductive Alkylations with Ketones Procedure E

An equivalent of a suitable primary amine and two equivalents of asuitable ketone are dissolved in methanol containing acetic acid. Thesolution is treated with an excess of sodium cyanoborohydride andagitated until sufficient product has been formed, typically for from1-5 days. The reaction mixture is then passed over a VARIAN BOND ELUTSCX™ (Varian, Harbor City, Calif., U.S.A.) ion exchange column which hasbeen preactivated with 10% acetic acid in methanol. The column is washedthoroughly with methanol and then the product is eluted with 2M ammoniain methanol. The secondary amine products are then isolated byconcentration of eluant.

The compounds of Examples 117 and 118 were prepared by PROCEDURE E.

EXAMPLE 117N-[2-methyl-3-(2-[N'-isopropylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.05 mMol ofN-[2-methyl-3-(2-aminoethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation X) and 0.1 mMol of acetone, the title compound wasprepared.

MS(m/e): 354(M+1)

EXAMPLE 118N-(2-methyl-3-(2-(N'-cyclohexylamino]ethyl)-1H-indol-5-yl]-4-fluorobenzamide

Beginning with 0.05 mMol ofN-[2-methyl-3-(2-aminoethyl)-1H-indol-5-yl]-4-fluorobenzamide(Preparation X) and 0.1 mMol of cyclohexanone, the title compound wasprepared.

MS(m/e): 394(M+1)

To demonstrate the use of the compounds of this invention in thetreatment of migraine, their ability to bind to the 5-HT_(1F) receptorsubtype was determined. The ability of the compounds of this inventionto bind to the 5-HT_(1F) receptor subtype was measured essentially asdescribed in N. Adham, et al., Proceedings of the National Academy ofSciences (USA), 90, 408-412 (1993).

Membrane Preparation: Membranes were prepared from transfected Ltk-cells which were grown to 100% confluency. The cells were washed twicewith phosphate-buffered saline, scraped from the culture dishes into 5mL of ice-cold phosphate-buffered saline, and centrifuged at 200×g for 5minutes at 4° C. The pellet was resuspended in 2.5 mL of ice-cold Trisbuffer (20 mM Tris HCl, pH=7.4 at 23° C., 5 mM EDTA) and homogenizedwith a Wheaton tissue grinder. The lysate was subsequently centrifugedat 200×g for 5 minutes at 4° C. to pellet large fragments which werediscarded. The supernatant was collected and centrifuged at 40,000×g for20 minutes at 4° C. The pellet resulting from this centrifugation waswashed once in ice-cold Tris wash buffer and resuspended in a finalbuffer containing 50 mM Tris HCl and 0.5 mM EDTA, pH=7.4 at 23° C.Membrane preparations were kept on ice and utilized within two hours forthe radioligand binding assays. Protein concentrations were determinedby the method of Bradford (Anal. Biochem., 72, 248-254 (1976)).

Radioligand Binding: [³ H-5-HT] binding was performed using slightmodifications of the 5-HT_(1D) assay conditions reported byHerrick-Davis and Titeler (J. Neurochem., 50, 1624-1631 (1988)) with theomission of masking ligands. Radioligand binding studies were achievedat 37° C. in a total volume of 250 μL of buffer (50 mM Tris, 10 mMMgCl₂, 0.2 mM EDTA, 10 μM pargyline, 0.1% ascorbate, pH=7.4 at 37° C.)in 96 well microtiter plates. Saturation studies were conducted using [³H]5-HT at 12 different concentrations ranging from 0.5 nM to 100 nM.Displacement studies were performed using 4.5-5.5 nM [³ H]5-HT. Thebinding profile of drugs in competition experiments was accomplishedusing 10-12 concentrations of compound. Incubation times were 30 minutesfor both saturation and displacement studies based upon initialinvestigations which determined equilibrium binding conditions.Nonspecific binding was defined in the presence of 10 μM 5-HT. Bindingwas initiated by the addition of 50 μL membrane homogenates (10-20 μg).The reaction was terminated by rapid filtration through presoaked (0.5%poylethyleneimine) filters using 48R Cell Brandel Harvester(Gaithersburg, Md.) Subsequently, filters were washed for 5 seconds withice cold buffer (50 mM Tris HCl, pH=7.4 at 4° C.), dried and placed intovials containing 2.5 mL Readi-Safe (Beckman, Fullerton, Calif.) andradioactivity was measured using a Beckman LS 5000TA liquidscintillation counter. The efficiency of counting of [³ H]5-HT averagedbetween 45-50%. Binding data was analyzed by computer-assisted nonlinearregression analysis (Accufit and Accucomp, Lunden Software, ChagrinFalls, Ohio). IC₅₀ values were converted to K_(i) values using theCheng-Prusoff equation (Biochem. Pharmacol., 22, 3099-3108 (1973). Allexperiments were performed in triplicate. Representative compounds ofthe present invention were found to have an affinity at the 5-HT_(1F)receptor of K_(i) ≦1.5 mM.

As was reported by R. L. Weinshank, et al., WO93/14201, the 5-HT_(1F)receptor is functionally coupled to a G-protein as measured by theability of serotonin and serotonergic drugs to inhibit forskolinstimulated cAMP production in NIH3T3 cells transfected with the5-HT_(1F) receptor. Adenylate cyclase activity was determined usingstandard techniques. A maximal effect is achieved by serotonin. AnE_(max) is determined by dividing the inhibition of a test compound bythe maximal effect and determining a percent inhibition. (N. Adham, etal., supra; R. L. Weinshank, et al., Proceedings of the National Academyof Sciences (USA), 89,3630-3634 (1992)), and the references citedtherein.

Measurement of cAMP formation

Transfected NIH3T3 cells (estimated Bmax from one point competitionstudies=488 fmol/mg of protein) were incubated in DMEM, 5 mMtheophylline, 10 mM HEPES (4-[2-hydroxyethyl]-1-piperazineethanesulfonicacid) and 10 μM pargyline for 20 minutes at 37° C., 5% CO₂. Drugdose-effect curves were then conducted by adding 6 different finalconcentrations of drug, followed immediately by the addition offorskolin (10 μM). Subsequently, the cells were incubated for anadditional 10 minutes at 37° C., 5% CO₂. The medium was aspirated andthe reaction was stopped by the addition of 100 mM HCl. To demonstratecompetitive antagonism, a dose-response curve for 5-HT was measured inparallel, using a fixed dose of methiothepin (0.32 μM). The plates werestored at 4° C. for 15 minutes and then centrifuged for 5 minutes at500×g to pellet cellular debris, and the supernatant was aliquoted andstored at -20° C. before assessment of cAMP formation byradioimmunoassay (cAMP radioimmunoassay kit; Advanced Magnetics,Cambridge, Mass.). Radioactivity was quantified using a Packard COBRAAuto Gamma counter, equipped with data reduction software.

The discovery that the pain associated with migraine and associateddisorders is inhibited by agonists of the 5-HT_(1F) receptor requiredthe analysis of data from diverse assays of pharmacological activity. Toestablish that the 5-HT_(1F) receptor subtype is responsible formediating neurogenic meningeal extravasation which leads to the pain ofmigraine, the binding affinity of a panel of compounds to serotoninreceptors was measured first, using standard procedures. For example,the ability of a compound to bind to the 5-HT_(1F) receptor subtype wasperformed as described supra. For comparison purposes, the bindingaffinities of compounds to the 5-HT_(1D)α, 5-HT_(1D)β, 5-HT_(1E) and5-HT_(1F) receptors were also determined as described supra, except thatdifferent cloned receptors were employed in place of the 5-HT_(1F)receptor clone employed therein. The same panel was then tested in thecAMP assay to determine their agonist or antagonist character at each ofthe 5-HT_(1D)α, 5-HT_(1D)β, 5-HT_(1E) and 5-HT_(1F) receptor subtypes.Finally, the ability of these compounds to inhibit neuronal proteinextravasation, a functional assay for migraine pain, was measured.

The panel of compounds used in this study represents distinct structuralclasses of compounds which were shown to exhibit a wide range ofaffinities for the serotonin receptors assayed. Additionally, the panelcompounds were shown to have a wide efficacy range in the neuronalprotein extravasation assay as well. The panel of compounds selected forthis study are described below.

Compound I3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamidebutane-1,4-dioate (1:1) (Sumatriptan succinate) ##STR12##

Sumatriptan succinate is coinercially available as Imitrex™ or may beprepared as described in U.S. Pat. No. 5,037,845, issued Aug. 6, 1991,which is herein incorporated by reference.

Compound II5-fluoro-3-<1-<2-<1-methyl-1H-pyrazol-4-yl>ethyl>-4-piperidinyl>-1H-indolehydrochloride ##STR13##

Compound II is described in U.S. Pat. No. 5,521,196, issued May 28,1996, which is herein incorporated by reference in its entirety.

Comnound III 5-hydroxy-3-(4-piperidinyl)-1H-indole oxalate ##STR14##

Compound III is available by the following procedure.

5-benzyloxy-3-[1,2,5,6-tetrahydro-4-pyridinyl]-1H-indole

Starting with 5.0 gm (22 mMol) 5-benzyloxyindole and 6.88 gm (45 mMol)4-piperidone.HCl.H₂ O, 6.53 gm (97.6%) of5-benzyloxy-3-[1,2,5,6-tetrahydro-4-pyridinyl]-1H-indole were recoveredas a light yellow solid by the procedure described in Preparation I. Thematerial was used in the subsequent step without further purification.

Hydrogenation/Hydrogenolysis

To a solution of 1.23 gm (4 mMol)5-benzyloxy-3-[1,2,5,6-tetrahydro-4-pyridinyl]-1H-indole in 50 mL 1:1tetrahydrofuran:ethanol were added 0.3 gm 5% palladium on carbon and thereaction mixture hydrogenated at ambient temperature for 18 hours withan initial hydrogen pressure of 60 p.s.i. The reaction mixture was thenfiltered through a celite pad and the filtrate concentrated underreduced pressure. The residue was converted to the oxalate salt and 0.98gm (80.0%) of Compound III were recovered as a brown foam.

m.p.=67° C.; MS(m/e): 216(M⁺); Calculated for C₁₃ H₁₆ N₂ O.C₂ H₂ O₄ :Theory: C, 58.81; H, 5.92; N, 9.14. Found: C, 58.70; H, 5.95; N, 9.39.

Compound IV 8-chloro-2-diethylamino-1,2,3,4-tetrahydronaphthalenehydrochloride ##STR15##

Compound IV is available by the following procedure.

8-chloro-2-tetralone

A mixture of 30.0 gm (0.176 mole) of o-chlorophenylacetic acid and 40.0mL of thionyl chloride was stirred at ambient temperature for 18 hours.The volatiles were then removed in vacuo to give 32.76 gm (99.0%) ofo-chlorophenylacetyl chloride as a transparent, pale yellow, mobileliquid.

NMR(CDCl₃): 7.5-7.1 (m, 4H), 4.2 (s, 2H).

To a slurry of 46.5 gm (0.348 mole) AlCl₃ in 400 mL dichloromethane at-78° C. was added a solution of 32.76 gm (0.174 mole) of the previouslyprepared o-chlorophenylacetyl chloride in 100 mL dichloromethanedropwise over 1 hour. The dry ice/acetone bath then was replaced with anice/water bath and ethylene was bubbled into the reaction mixture duringwhich time the temperature rose to 15° C. The ethylene addition wasdiscontinued at the end of the exotherm and the reaction mixture wasstirred at about 5° C. for 4 hours. Ice was then added to the reactionmixture to destroy aluminum complexes. Upon termination of the exotherm,the reaction mixture was diluted with 500 mL of water and stirredvigorously until all solids had dissolved. The phases were separated andthe organic phase was washed with 3×400 mL 1N hydrochloric acid and2×400 mL saturated aqueous sodium bicarbonate. The remaining organicphase was then dried over sodium sulfate and concentrated in vacuo togive a pale orange residue. The residue was dissolved in 1:1hexane:diethyl ether and was poured over a flash silica column which wasthen eluted with 1:1 hexane:diethyl ether to give a light yellow residuewhich was crystallized from 4:1 hexane:diethyl ether to give 10.55 gm ofthe title compound.

NMR(CDCl₃): 7.5-7.2 (m, 3H), 3.7 (s, 2H), 3.3-3.0 (t, J=7 Hz, 2H),2.8-2.4 (t, J=7 Hz, 2H). MS: 180(60), 165(9), 138(100), 117(52),115(50), 103(48), 89(20), 76(25), 74(18), 63(30), 57(9), 52(28), 51(20),42(6), 39(32). IR(nujol mull): 2950 cm⁻¹, 2927 cm⁻¹, 1708 cm⁻¹, 1464cm⁻¹, 1450 cm⁻¹, 1169 cm⁻¹, 1114 cm¹.

Reductive Amination

To a solution of 0.5 gm (2.78 mMol) 8-chloro-2-tetralone in 25 mLcyclohexane were added 1.4 mL (13.9 mMol) diethylamine followed by 0.1gm p-toluenesulfonic acid monohydrate. The reaction mixture was thenheated at reflux with constant water removal (Dean-Stark Trap) for 18hours. The reaction mixture was then cooled to ambient and the volatilesremoved under reduced pressure. The residue was then dissolved in 15 mLmethanol to which were then added 1.5 mL acetic acid followed by theportionwise addition of 0.5 gm sodium borohydride. The reaction mixturewas then stirred for 1 hour at ambient.

The reaction mixture was then diluted with 20 mL 10% HCl and stirred foran additional hour. The mixture was then extracted with diethyl etherand the remaining aqueous phase was poured over ice, made basic withammonium hydroxide and extracted well with dichloromethane. Theseextracts were combined, dried over sodium sulfate and concentrated underreduced pressure. The residue was redissolved in dichloromethane andsubjected to chromatography over basic alumina, eluting withdichloromethane. Fractions shown to contain product were combined andconcentrated under reduced pressure. The residual oil was dissolved indiethyl ether and the solution saturated with hydrogen chloride. Theviscous residue was crystallized from acetone/diethyl ether to give 0.20gm (23.2%) of Compound IV as colorless crystals.

m.p.=158-159° C.; MS(m/e): 273; Calculated for C₁₄ H₂₁ NCl.HCl: Theory:C, 61.32; H, 7.72; N, 5.11. Found: C, 61.62; H, 7.94; N. 5.03.

Compound V 6-hydroxy-3-dimethylamino-1,2,3,4-tetrahydrocarbazole##STR16##

Compound V is available by the following procedure.

4-dimethylamino-1-cyclohexanone Ethylene Ketal

To a solution of 5.0 gm (32 mMol) 1,4-cyclohexanedione mono-ethyleneketal and 10.80 gm (240 mMol) dimethylamine were added 2.0 mL aceticacid and the mixture was stirred at 0° C. for 1.5 hours. To thissolution were then added 3.62 gm (58 mMol) sodium cyanoborohydride andthe reaction stirred for an additional hour at ambient. The pH of thereaction mixture was adjusted to ˜7 with 16 mL acetic acid and stirred18 hours at ambient. The volatiles were removed under reduced pressureand the residue dissolved in cold 5% tartaric acid solution and then theaqueous phase was made basic with 5N sodium hydroxide. This aqueousphase was extracted well with dichloromethane. These organic extractswere combined and concentrated under reduced pressure to give 5.04 gm(85%) of the title compound as an oil.

4-dimethylamino-1-cyclohexanone

4.96 gm (26.8 mMol) 4-dimethylamino-1-cyclohexanone ethylene ketal weredissolved in 50 mL formic acid and the solution stirred at reflux for 18hours. The reaction mixture was then cooled to ambient and the volatilesremoved under reduced pressure to give 3.78 gm (100%) of the titlecompound.

6-benzyloxy-3-dimethylamino-1,2,3,4-tetrahydrocarbazole

To a solution of 3.78 gm (26.8 mMol) 4-dimethylamino-1-cyclohexanone and6.69 gm (26.8 mMol) 4-benzyloxyphenylhydrazine hydrochloride in 50 mLethanol were added 2.17 mL (26.8 mMol) pyridine. To this solution wereadded 5×10 mL portions of water and the reaction mixture then stored at0° C. for 18 hours. The reaction mixture was then diluted with anadditional 50 mL of water and the mixture extracted well withdichloromethane. The combined organic extracts were dried over sodiumsulfate and the volatiles removed under reduced pressure. The residualoil was subjected to flash silica gel chromatography, eluting with 9:1chloroform:methanol. Fractions shown to contain the desired product werecombined and concentrated under reduced pressure to give 2.14 gm (24.9%)of the title compound.

Hydrogenolysis

To a solution of 2.14 gm (6.7 mMol)6-benzyloxy-3-dimethylamino-1,2,3,4-tetrahydrocarbazole in 50 mL ethanolwere added 0.20 gm 10% palladium on carbon and the reaction mixture washydrogenated at ambient temperature with an initial hydrogen pressure of40 p.s.i. After 5 hours an additional charge of 0.20 gm 10% palladium oncarbon were added and the reaction mixture repressurized with hydrogento 40 p.s.i. for 4 hours. The reaction mixture was then filtered througha pad of celite and the filtrate concentrated under reduced pressure.The residue was subjected to Florisil chromatography, eluting with 9:1chloroform:methanol. Fractions shown to contain the desired compoundwere combined and concentrated under reduced pressure. The residue wasagain subjected to Florisil chromatography, eluting with a gradientconsisting of chloroform containing 2-10% methanol. Fractions shown tocontain product were combined and concetnrated under reduced pressure togive Compound V as a crystalline solid.

MS(m/e): 230(M⁺); Calculated for C₁₄ H₁₈ N₂ O: Theory: C, 73.01; H,7.88; N, 12.16. Found: C, 72.75; H, 7.83; N, 11.97.

Binding Assays

The binding affinities of compounds for various serotonin receptors weredetermined essentially as described above except that different clonedreceptors are employed in place of the 5-HT_(1F) receptor clone employedtherein. The results of these binding experiments are summarized inTable II.

                  TABLE II                                                        ______________________________________                                        BINDING TO SEROTONIN (5-HT.sub.1) RECEPTOR SUBTYPES (K.sub.i nM)                Compound     5-HT.sub.1Dα                                                                     5-HT.sub.1Dβ                                                                      5-HT.sub.1E                                                                         5-HT.sub.1F                            ______________________________________                                        I          4.8      9.6        2520.0                                                                              25.7                                       II 21.7 53.6 50.3 2.5                                                         III 163.2 196.5 3.9 22.0                                                      IV 13.5 145.3 813.0 129.2                                                     V 791.0 1683.0 73.6 10.3                                                    ______________________________________                                    

cAMP Formation

All of the compounds of the panel were tested in the cAMP formationassay described supra and all were found to be agonists of the 5-HT_(1F)receptor.

Protein Extravasation

Harlan Sprague-Dawley rats (225-325 g) or guinea pigs from Charles RiverLaboratories (225-325 g) were anesthetized with sodium pentobarbitalintraperitoneally (65 mg/kg or 45 mg/kg respectively) and placed in astereotaxic frame (David Kopf Instruments) with the incisor bar set at-3.5 mm for rats or -4.0 mm for guinea pigs. Following a midline sagitalscalp incision, two pairs of bilateral holes were drilled through theskull (6 mm posteriorly, 2.0 and 4.0 mm laterally in rats; 4 mmposteriorly and 3.2 and 5.2 mm laterally in guinea pigs, all coordinatesreferenced to bregma). Pairs of stainless steel stimulating electrodes(Rhodes Medical Systems, Inc.) were lowered through the holes in bothhemispheres to a depth of 9 mm (rats) or 10.5 mm (guinea pigs) fromdura.

The femoral vein was exposed and a dose of the test compound wasinjected intravenously (1 mL/kg). Approximately 7 minutes later, a 50mg/kg dose of Evans Blue, a fluorescent dye, was also injectedintravenously. The Evans Blue complexed with proteins in the blood andfunctioned as a marker for protein extravasation. Exactly 10 minutespost-injection of the test compound, the left trigeminal ganglion wasstimulated for 3 minutes at a current intensity of 1.0 mA (5 Hz, 4 msecduration) with a Model 273 potentiostat/galvanostat (EG&G PrincetonApplied Research).

Fifteen minutes following stimulation, the animals were killed andexsanguinated with 20 mL of saline. The top of the skull was removed tofacilitate the collection of the dural membranes. The membrane sampleswere removed from both hemispheres, rinsed with water, and spread flaton microscopic slides. Once dried, the tissues were coverslipped with a70% glycerol/water solution.

A fluorescence microscope (Zeiss) equipped with a grating monochromatorand a spectrophotometer was used to quantify the amount of Evans Bluedye in each sample. An excitation wavelength of approximately 535 nm wasutilized and the emission intensity at 600 nm was determined. Themicroscope was equipped with a motorized stage and also interfaced witha personal computer. This facilitated the computer-controlled movementof the stage with fluorescence measurements at 25 points (500 μm steps)on each dural sample. The mean and standard deviation of themeasurements was determined by the computer.

The extravasation induced by the electrical stimulation of thetrigeminal ganglion was an ipsilateral effect (i.e. occurs only on theside of the dura in which the trigeminal ganglion was stimulated). Thisallows the other (unstimulated) half of the dura to be used as acontrol. The ratio of the amount of extravasation in the dura from thestimulated side comnpared to the unstimulated side dura was calculated.Saline controls yielded a ratio of approximately 2.0 in rats and 1.8 inguinea pigs. In contrast, a compound which effectively prevented theextravasation in the dura from the stimulated side would have a ratio ofapproximately 1.0. A dose-response curve was generated and the dose thatinhibited the extravasation by 50% (ID₅₀) was approximated. This data ispresented in Table III.

                  TABLE III                                                       ______________________________________                                        Inhibition of Protein Extravasation (ID.sub.50 mMol/kg)                                         i.v. ID.sub.50                                                Compound (mMol/kg)                                                          ______________________________________                                        I             2.6 × 10.sup.-8                                             II .sup. 8.6 × 10.sup.-10                                               III 8.9 × 10.sup.-9                                                     IV 1.2 × 10.sup.-7                                                      V 8.7 × 10.sup.-9                                                     ______________________________________                                    

To determine the relationship of binding at various serotonin receptorsto inhibitio n of neuronal protein extravasation, the binding affinityof all of the compounds to each of the 5-HT_(1D)α, 5-HT_(1D)β, 5-HT_(1E)and 5-HT_(1F) receptors was plotted against their ID₅₀ in the proteinextravasation model. A linear regression analysis was performed on eachset of data and a correlation factor, R², calculated. The results ofthis analysis are suetarized in Table IV.

                  TABLE IV                                                        ______________________________________                                        Correlation Factor (R.sup.2) for Specific 5-HT.sub.1 Subtype Binding           Affinity vs Inhibition of Protein Extravasation                                     5-HT.sub.1 Subtype                                                                       Correlation Factor (R.sup.2)                                ______________________________________                                        5-HT.sub.1Dα                                                                          0.07                                                              5-HT.sub.1Dβ 0.001                                                       5-HT.sub.1E 0.31                                                              5-HT.sub.1F 0.94                                                            ______________________________________                                    

An ideally linear relationship would generate a correlation factor of1.0, indicating a cause and effect relationship between the twovariables. The experimentally determined correlation factor betweeninhibition of neuronal protein extravasation and 5-HT_(1F) bindingaffinity is 0.94. This nearly ideal dependence of the ID₅₀ in theprotein extravasation model on binding affinity to the 5-HT_(1F)receptor clearly demonstrates that the 5-HT_(1F) receptor mediates theinhibition of protein extravasation resulting from stimulation of thetrigeminal ganglia.

The compounds of the present invention are distinguished fromstructurally similar tryptamines by their lack of vasoconstrictiveproperties. The lack of vasoconstrictive activity exhibited by thecompounds of the present invention was determined by measuring theirability to mediate vasoconstriction in the rabbit saphenous vein.

Rabbit Saphenous Vein Contraction

Male New Zealand White rabbits (3-6 lbs) (Hazleton, Kalamazoo, Mich.)were sacrificed by a lethal dose of sodium pentobarbital (325 mg)injected into the ear vein. Tissues were dissected free of connectivetissue, cannulated in situ with polyethylene tubing (PE50, outsidediameter=0.97 mm) and placed in petri dishes containing Kreb'sbicarbonate buffer (described infra). The tips of two 30-gauge stainlesssteel hypodermic needles bent into an L-shape were slipped into thepolyetylene tubing. Vessels were gently pushed from the cannula onto theneedles. The needles were then separated so that the lower one wasattached with thread to a stationary glass rod and the upper one wastied with thread to the transducer.

Tissues were mounted in organ baths containing 10 mL of modified Krebs'solution of the following composition: 118.2 mMol NaCl, 4.6 mMol KCl,1.6 mMol CaCl₂.H₂ O, 1.2 mMol KH₂ PO₄, 1.2 mMol MgSO₄, 10.0 mMoldextrose and 24.8 mMol NaHCO₃. Tissue bath solutions were maintained at37° C. and aerated with 95% O₂ and 5% CO₂. An initial optimum restingforce of 1 gm was applied to the saphenous vein. Isometric contractionswere recorded as changes in grams of force on a Beckman Dynograph withStatham UC-3 transducers and microscale accessory attachments. Tissueswere allowed to equilibrate 1 to 2 hours before exposure to drugs.Cumulative agonist concentration-response curves were generated intissues and no tissue was used to generate more than two agonistconcentration-response curves. All results were expressed as a mean EC₅₀and the maximal response was expressed as a percentage of the responseto 67 mM KCl administered initially in each tissue.

While it is possible to administer a compound employed in the methods ofthis invention directly without any formulation, the compounds areusually administered in the form of pharmaceutical compositionscomprising a pharmaceutically acceptable excipient and at least oneactive ingredient. These compositions can be administered by a varietyof routes including oral, rectal, transdermal, subcutaneous,intravenous, intramuscular, and intranasal. Many of the compoundsemployed in the methods of this invention are effective as bothinjectable and oral compositions. Such compositions are prepared in amanner well known in the pharmaceutical art and comprise at least oneactive compound. See, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, (16thed. 1980).

In making the compositions employed in the present invention the activeingredient is usually mixed with an excipient, diluted by an excipientor enclosed within such a carrier which can be in the form of a capsule,sachet, paper or other container. When the excipient serves as adiluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing forexample up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxybenzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 0.05 to about 100 mg, more usually about1.0 to about 30 mg, of the active ingredient. The term "unit dosageform" refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The active compounds are generally effective over a wide dosage range.For examples, dosages per day normally fall within the range of about0.01 to about 30 mg/kg of body weight. In the treatment of adult humans,the range of about 0.1 to about 15 mg/kg/day, in single or divided dose,is especially preferred. However, it will be understood that the amountof the compound actually administered will be determined by a physician,in the light of the relevant circumstances, including the condition tobe treated, the chosen route of administration, the actual compound orcompounds administered, the age, weight, and response of the individualpatient, and the severity of the patient's symptoms, and therefore theabove dosage ranges are not intended to limit the scope of the inventionin any way. In some instances dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed without causing any harmful side effect,provided that such larger doses are first divided into several smallerdoses for administration throughout the day.

Formulation Example 1

Hard gelatin capsules containing the following ingredients are prepared:

    ______________________________________                                                          Quantity                                                      Ingredient (mg/capsule)                                                     ______________________________________                                        Compound of Example 1                                                                           30.0                                                          Starch 305.0                                                                  Magnesium stearate 5.0                                                      ______________________________________                                    

The above ingredients are mixed and filled into hard gelatin capsules in340 mg quantities.

Formulation Example 2

A tablet formula is prepared using the ingredients below:

    ______________________________________                                                          Quantity                                                      Ingredient (mg/tablet)                                                      ______________________________________                                        Compound of Example 106                                                                         25.0                                                          Cellulose, microcrystalline 200.0                                             Colloidal silicon dioxide 10.0                                                Stearic acid 5.0                                                            ______________________________________                                    

The components are blended and compressed to form tablets, each weighing240 mg.

Another preferred formulation employed in the methods of the presentinvention employs transdermal delivery devices ("patches"). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See. e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

Frequently, it will be desirable or necessary to introduce thepharmaceutical composition to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system, used for the transport ofbiological factors to specific anatomical regions of the body, isdescribed in U.S. Pat. No. 5,011,472, issued Apr. 30, 1991, which isherein incorporated by reference.

Indirect techniques, which are generally preferred, usually involveformulating the compositions to provide for drug latentiation by theconversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.Latentiation is generally achieved through blocking of the hydroxy,carbonyl, sulfate, and primary amine groups present on the drug torender the drug more lipid soluble and amenable to transportation acrossthe blood-brain barrier. Alternatively, the delivery of hydrophilicdrugs may be enhanced by intra-arterial infusion of hypertonic solutionswhich can transiently open the blood-brain barrier.

The type of formulation employed for the administration of the compoundsemployed in the methods of the present invention may be dictated by theparticular compounds employed, the type of pharmacokinetic profiledesired from the route of administration and the compound(s), and thestate of the patient.

We claim:
 1. The compound1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide.